EBNA1 inhibitors and their method of use

ABSTRACT

The invention provides EBNA1 inhibitors, and pharmaceutical compositions comprising the same, that are useful for the treatment of diseases caused by EBNA1 activity such as, but not limited to, cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus and/or rheumatoid arthritis. The compounds and compositions of the invention are further useful for the treatment of diseases caused by latent Epstein-Barr Virus (EBV) infection. The compounds and compositions of the invention are further useful for the treatment of diseases caused by lytic EBV infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. §371 national phase application from,and claims priority to, International Application No. PCT/US2014/065765,filed Nov. 14, 2014, and published under PCT Article 21(2) in English,which claims priority under 35 U.S.C. §119(e) to U.S. ProvisionalApplication No. 61/904,555, filed Nov. 15, 2013, all of whichapplications are incorporated by reference herein in their entireties.

STATEMENT OF FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grant number5R43AI079928, awarded by the National Institutes of Health (NIAID) toVironika, LLC; and grant number 1R21NS063906, awarded by the NationalInstitutes of Health (NINDS) to The Wistar Institute. The government hascertain rights in the invention.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention describes compounds and methods useful as EBNA1inhibitors, e.g., useful for the treatment of diseases caused by EBNA1activity. The present invention also describes compounds and methodsuseful as EBNA1 inhibitors, e.g., useful for the treatment of diseasescaused by the Epstein-Barr Virus (EBV).

Related Art

EBV is a human gamma-herpesvirus that infects over 90% of the adultpopulation worldwide [Young, L. S. and A. B. Rickinson, Epstein-Barrvirus: 40 years on, Nat. Rev. Cancer, 2004, 4:757-68; Rickinson, A. B.and E. Kieff, Epstein-Barr Virus, in Fields Virology, Third Edition,1996, Lippincott-Raven Publishers, pp. 2397-446]. In combination withknown and unknown cofactors, especially immunosuppression, EBV infectionconstitutes a high carcinogenic risk. EBV has been classified by theWorld Health Organization as a class I human carcinogen because of itscausal association with Burkitt's lymphoma, nasopharyngeal carcinoma,˜50% of all Hodgkin's lymphoma, gastric carcinoma, angiocentric T/NKlymphoma, and lymphoproliferative disorders of the immunosuppressed. Ithas been estimated that EBV is responsible for ˜1% of all human cancersworldwide [Parkin, D. M., F. Bray, J. Ferlay, and P. Pisani (2005)Global Cancer Statistics, 2002, Cancer J. Clin. 55:75-108]. Theoncogenic potential of EBV is readily demonstrated in vitro by itscapacity to immortalize primary B-lymphocytes in culture and in vivo byits ability to drive infected B-cells into aggressive lymphoblasticlymphomas in immunocompromised hosts.

EBV, like other herpesviruses, has a latent and lytic replication cycle.While the EBV lytic cycle is essential for viral transmission andincreases risk of EBV-associated malignancy, it is the latent viralinfection that is oncogenic [Thorley-Lawson, D. A. and A. Gross,Persistence of the Epstein-Barr virus and the origins of associatedlymphomas, N. Engl. J. Med., 2004. 350:1328-37]. The latent virusexpresses a limited set of viral genes that stimulate cellularproliferation and survival. Clinically available inhibitors ofherpesvirus DNA polymerases, including variants of acyclovir (e.g.ganciclovir) and phosphonoacetic acid (e.g. foscarnet), have at leastpartial inhibitory activity against EBV lytic replication. However, noneof the available herpesvirus antivirals are effective at blocking thevirus from progressing to a latent infection or eliminating latentinfection. Primary infections with EBV can evoke a robust, sometimesdebilitating, immune response referred to as infectious mononucleosis(IM) [Vetsika, E. K. and M. Callan, Infectious mononucleosis andEpstein-Barr virus, Expert Rev. Mol. Med., 2004. 6:1-16]. Despite thisrobust immune reaction, the virus efficiently establishes latentinfection in B-lymphocytes, where the virus can reside in long-livedmemory B-cells [Babcock, G. J., L. L. Decker, M. Volk, and D. A.Thorley-Lawson, EBV persistence in memory B cells in vivo, Immunity,1998, 9:395-404]. In some circumstances, latent infection can also beestablished in T-lymphocytes and epithelial cells. During latency, thevirus does not produce infectious particles, and viral gene expressionis limited to a subset of transcripts with growth-transforming andanti-apoptotic functions that contribute to EBV carcinogenesis. Thus, noexisting anti-viral drug or immunological response can block theestablishment of an EBV latent infection, which has the potential todrive lymphoid and epithelial cell oncogenic growth transformation.

Numerous studies have demonstrated that Epstein-Barr Nuclear Antigen 1(EBNA1) is an ideal target for elimination of latent infection andtreatment of EBV-associated disease. First, EBNA1 is expressed in allEBV-positive tumors [Leight, E. R. and B. Sugden, EBNA-1: a proteinpivotal to latent infection by Epstein-Barr virus, Rev. Med. Virol.,2000, 10:83-100; Altmann, M., D. Pich, R. Ruiss, J. Wang, B. Sugden, andW. Hammerschmidt, Transcriptional activation by EBV nuclear antigen 1 isessential for the expression of EBV's transforming genes, Proc. Natl.Acad. Sci. USA, 2006, 103:14188-93]. Second, EBNA1 is required forimmortalization of primary B-lymphocytes and for the stable maintenanceof the EBV genome in latently infected cells [Humme, S., G. Reisbach, R.Feederle, H. J. Delecluse, K. Bousset, W. Hammerschmidt, and A.Schepers, The EBV nuclear antigen 1 (EBNA1) enhances B cellimmortalization several thousand-fold, Proc. Natl. Acad. Sci. USA, 2003,100:10989-94]. Third, genetic disruption of EBNA1 blocks the ability ofEBV to immortalize primary human B-lymphocytes and causes loss of cellviability in previously established EBV-positive cell lines [Lee, M. A.,M. E. Diamond, and J. L. Yates, Genetic evidence that EBNA-1 is neededfor efficient, stable latent infection by Epstein-Barr virus, J. Virol.,1999. 73:2974-82]. Fourth, biochemical disruption of EBNA1 foldingblocks the establishment of EBV latent infection. HSP90 inhibitors causethe selective killing of EBV⁺ B-cells and block lymphomagenesis in mousemodels [Sun, X., E. A. Barlow, S. Ma S. R. Hagemeier, S. J. Duellman, R.R. Burgess, J. Tellam, R. Khanna, and S. C. Kenney, 2010, Hsp90inhibitors block outgrowth of EBV-infected malignant cells in vitro andin vivo through an EBNA1-dependent mechanism, Proc. Natl. Acad. Sci.USA, 107:3146-51]. Fifth, EBNA1 is a noncellular viral oncoprotein thatis functionally and structurally well characterized. Thethree-dimensional structure of EBNA1 bound to its cognate DNA sequencehas been solved by X-ray crystallography [Bochkarev, A., J. A. Barwell,R. A. Pfuetzner, E. Bochkareva, L. Frappier, and A. M. Edwards, Crystalstructure of the DNA-binding domain of the Epstein-Barr virusorigin-binding protein, EBNA1, bound to DNA, Cell, 1996, 84:791-800;Bochkarev, A., J. A. Barwell, R. A. Pfuetzner, W. Furey, A. M. Edwards,and L. Frappier, Crystal structure of the DNA binding domain of theEpstein-Barr virus origin binding protein EBNA-1, Cell, 1995, 83:39-46;Bochkarev A, Bochkareva E, Frappier L, Edwards A M. The 2.2 Å structureof a permanganate-sensitive DNA site bound by the Epstein-Barr virusorigin binding protein, EBNA1. J Mol Biol, 1998. 284:1273-78]. Analysisof the DNA binding domain reveals that EBNA1 protein is druggable, withseveral deep pockets and channels within the DNA binding domain that arepredicted to disrupt DNA binding when bound to small molecules. Sixth,targeting a non-self viral-encoded protein for inhibition mitigates thepotential risk of inherent toxicity. EBNA1 has a unique structural foldthat is distinct from all known cellular DNA binding and replicationproteins [Sun X, Barlow E A, Ma S, Hagemeier S R, Duellman S J, BurgessR R, Tellam J, Khanna R, Kenney S C. (2010) Hsp90 inhibitors blockoutgrowth of EBV-infected malignant cells in vitro and in vivo throughan EBNA1-dependent mechanism. Proc Natl Acad Sci USA 107:3146-51;Bochkarev A, Barwell J A, Pfuetzner R A, Bochkareva E, Frappier L,Edwards A M. Crystal structure of the DNA-binding domain of theEpstein-Barr virus origin-binding protein, EBNA1, bound to DNA. Cell,1996. 84:791-800; Bochkarev A, Barwell J A, Pfuetzner R A, Furey W,Edwards A M, Frappier L. Crystal structure of the DNA binding domain ofthe Epstein-Barr virus origin binding protein EBNA-1. Cell, 1995.83:39-46]. Finally, the EBNA1 DNA binding function is essential for allknown EBNA1 functions, including genome maintenance, DNA replication,transcription regulation, and host-cell survival [Leight, E. R. and B.Sugden, EBNA-1: a protein pivotal to latent infection by Epstein-Barrvirus. Rev Med Virol, 2000. 10:83-100. Altmann M, Pich D, Ruiss R, WangJ, Sugden B, Hammerschmidt W. Transcriptional activation by EBV nuclearantigen 1 is essential for the expression of EBV's transforming genes.Proc Natl Acad Sci USA, 2006. 103:14188-93; Rawlins D R, Milman G,Hayward S D, Hayward G S. Sequence-specific DNA binding of theEpstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in theplasmid maintenance region. Cell, 1985. 42:859-68; Ritzi M, Tillack K,Gerhardt J, Ott E, Humme S, Kremmer E, Hammerschmidt W, Schepers A.Complex protein-DNA dynamics at the latent origin of DNA replication ofEpstein-Barr virus. J Cell Sci, 2003. 116:3971-84; Schepers A, Ritzi M,Bousset K, Kremmer E, Yates J L, Harwood J, Diffley J F, HammerschmidtW. Human origin recognition complex binds to the region of the latentorigin of DNA replication of Epstein-Barr virus. EMBO J, 2001.20:4588-602]. Collectively, these studies demonstrate that EBNA1-DNAbinding domain is an ideal and validated target for inhibition ofEBV-latent infection and treatment of EBV-associated malignancies.

EBV plays a causative role in the tumorigenesis for a number of cancersincluding nasopharyngeal carcinoma, gastric carcinomas, non-hodgkinlymphoma (anaplastic large-cell lymphoma, angioimmunoblastic T-celllymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt'slymphoma, reticuloendotheliosis, reticulosis, microglioma, diffuse largeB-cell lymphoma, extranodal T/NK lymphoma/angiocentric lymphoma,follicular lymphoma, immunoblastic lymphoma, mucosa-associated lymphatictissue lymphoma, B-cell chronic lymphocytic leukemia, mantle celllymphoma, mediastinal large B cell lymphoma, lymphoplasmactic lymphoma,nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma,intravascular large B-cell lymphoma, primary effusion lymphoma,lyphomatoid granulomatosis, angioimmunoblastic lymphadenopathy),leiomyosarcomas, X-linked lymphoproliferative disease, post-transplantlymphoproliferative disorders, Hodgkin's lymphoma and breast cancer. EBVhas been classified as a class I human carcinogen responsible for atleast 1% of all human cancer by the World Health Organization.EBV-associated malignancies account for more than 100,000 new cancercases each year in the United States. An inhibitor of EBNA1 would changecurrent clinical practice and be valuable for therapeutic treatment ofEBV-associated diseases. Currently, nucleoside analogues (aciclovir,ganciclovir, foscarnet) can be used to treat lytic EBV infection andpathologies related to lytic EBV infection. However, these generalanti-viral drugs are not specific for lytic EBV infection, and carry therisk of severe adverse effects. To date, no effective treatments existfor latent EBV infection, no treatment exists for pathologies related tolatent EBV infection, and no treatments exist for the treatment ofdiseases associated with EBNA1.

EBV infection and EBNA1 have also been implicated in infectiousmononucleosis [Henle W, Henle G. Epstein-Barr virus and infectiousmononucleosis, N Engl J Med. 1973. 288:263-64; Vetsika E K, Callan M.Infectious mononucleosis and Epstein-Barr virus, Expert Rev Mol Med.2004 6:1-16], chronic fatigue syndrome (CFS) [Watt T, Oberfoell S,Balise R, Lunn M R, Kar A K, Merrihew L, Bhangoo M S, Montoya J G.Response to valganciclovir in chronic fatigue syndrome patients withhuman herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J MedVirol. 2012, 84:1967-74; Natelson B H, Ye N, Moul D E, Jenkins F J, OrenD A, Tapp W N, Cheng Y C. High titers of anti-Epstein-Barr virus DNApolymerase are found in patients with severe fatiguing illness. J MedVirol. 1994. 42:42-6; Wallace H L 2nd, Natelson B, Gause W, Hay J. Humanherpesviruses in chronic fatigue syndrome. Clin Diagn Lab Immunol. 19996:216-23], multiple sclerosis [Tselis A. Epstein-Barr virus cause ofmultiple sclerosis, Curr Opin Rheumatol. 2012. 24:424-28; Lucas R M,Hughes A M, Lay M L, Ponsonby A L, Dwyer D E, Taylor B V, Pender M P.Epstein-Barr virus and multiple sclerosis, J Neurol NeurosurgPsychiatry. 2011. 82:1142-48; Ascherio A, Munger K L. Epstein-barr virusinfection and multiple sclerosis: a review, J Neuroimmune Pharmacol.2010. 3:271-77], systemic lupus erythematosus [Draborg A H, Duus K,Houen G. Epstein-Barr virus and systemic lupus erythematosus, Clin DevImmunol. 2012: 370516; Doria A, Canova M, Tonon M, Zen M, Rampudda E,Bassi N, Atzeni F, Zampieri S, Ghirardello A. Infections as triggers andcomplications of systemic lupus erythematosus, Autoimmun Rev. 2008.8:24-28; Poole B D, Scofield R H, Harley J B, James J A. Epstein-Barrvirus and molecular mimicry in systemic lupus erythematosus.Autoimmunity. 2006 39:63-70], and rheumatoid arthritis [Lossius A,Johansen J N, Torkildsen Ø, Vartdal F, Holmøy T. Epstein-Barr virus insystemic lupus erythematosus, rheumatoid arthritis and multiplesclerosis—association and causation. Viruses. 2012. 4:3701-30;Balandraud N, Roudier J, Roudier C. Epstein-Barr virus and rheumatoidarthritis, Autoimmun Rev. 2004 3:362-67; Oliver J E, Silman A J. Riskfactors for the development of rheumatoid arthritis. Scand J Rheumatol.2006. 35:169-74]. Treatment with compounds that prevent EBV infectionwould provide therapeutic relief to patients suffering from infectiousmononucleosis, multiple sclerosis, systemic lupus erythematosus, andrheumatoid arthritis. Further, treatment with compounds that preventlytic EBV infection would provide therapeutic relief to patientssuffering from infectious mononucleosis, multiple sclerosis, systemiclupus erythematosus, and rheumatoid arthritis. Further, treatment withcompounds that prevent latent EBV infection would provide therapeuticrelief to patients suffering from infectious mononucleosis, chronicfatigue syndrome, multiple sclerosis, systemic lupus erythematosus, andrheumatoid arthritis. Treatment with compounds that inhibit EBNA1 wouldprovide therapeutic relief for suffering from infectious mononucleosis,chronic fatigue syndrome, multiple sclerosis, systemic lupuserythematosus, and rheumatoid arthritis. To date, however, no effectivespecific treatments exist for lytic EBV infection and no specifictreatment exists for pathologies related to lytic EBV infection. Inaddition, to date, however, no effective treatments exist for latent EBVinfection, no treatment exists for pathologies related to latent EBVinfection, and no treatments exist for the treatment of diseasesassociated with EBNA1.

There is a long felt need for new treatments that are bothdisease-modifying and effective in treating patients that are refractoryto current treatments for diseases and conditions associated with EBVinfection such as nasopharyngeal carcinoma, gastric carcinomas,non-hodgkin lymphoma, anaplastic large-cell lymphoma, angioimmunoblasticT-cell lymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma,Burkitt's lymphoma, reticuloendotheliosis, reticulosis, microglioma,diffuse large B-cell lymphoma, extranodal T/NK lymphoma/angiocentriclymphoma, follicular lymphoma, immunoblastic lymphoma, mucosa-associatedlymphatic tissue lymphoma, B-cell chronic lymphocytic leukemia, mantlecell lymphoma, mediastinal large B cell lymphoma, lymphoplasmacticlymphoma, nodal marginal zone B cell lymphoma, splenic marginal zonelymphoma, intravascular large B-cell lymphoma, primary effusionlymphoma, lyphomatoid granulomatosis, angioimmunoblasticlymphadenopathy, leiomyosarcomas, X-linked lymphoproliferative disease,post-transplant lymphoproliferative disorders, Hodgkin's lymphoma andbreast cancer. There is also a long felt need for new treatments thatare both disease-modifying and effective in treating patients that arerefractory to current treatments for infectious mononucleosis. There isalso a long felt need for new treatments that are both disease-modifyingand effective in treating patients that are refractory to currenttreatments for chronic fatigues syndrome. There is also a long felt needfor new treatments that are both disease-modifying and effective intreating patients that are refractory to current treatments for multiplesclerosis. There is also a long felt need for new treatments that areboth disease-modifying and effective in treating patients that arerefractory to current treatments for systemic lupus erythematosus. Thereis also a long felt need for new treatments that are bothdisease-modifying and effective in treating patients that are refractoryto current treatments for rheumatoid arthritis. There is also a clearand present need for the treatment of EBV infection, and there is a longfelt need for treatments that can specifically block lytic EBVinfection. There is a long felt need for treatments that can blocklatent EBV infection. There is also a clear and present need for newtreatments that are both disease-modifying and effective in treatingdiseases associated with EBNA1.

The present invention addresses the need to identify new treatments fordiseases and conditions associated with EBV infection such as infectiousmononucleosis, chronic fatigue syndrome, multiple sclerosis, systemiclupus erythematosus, and rheumatoid arthritis, and cancer, includingnasopharyngeal carcinoma, gastric carcinomas, non-hodgkin lymphoma(anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma,hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt's lymphoma,reticuloendotheliosis, reticulosis, microglioma, diffuse large B-celllymphoma, extranodal T/NK lymphoma/angiocentric lymphoma, follicularlymphoma, immunoblastic lymphoma, mucosa-associated lymphatic tissuelymphoma, B-cell chronic lymphocytic leukemia, mantle cell lymphoma,mediastinal large B cell lymphoma, lymphoplasmactic lymphoma, nodalmarginal zone B cell lymphoma, splenic marginal zone lymphoma,intravascular large B-cell lymphoma, primary effusion lymphoma,lyphomatoid granulomatosis, angioimmunoblastic lymphadenopathy),leiomyosarcomas, X-linked lymphoproliferative disease, post-transplantlymphoproliferative disorders, Hodgkin's lymphoma, and breast cancer byidentifying novel EBNA1 inhibitors useful as therapeutic agents and intherapeutic compositions.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward EBNA1 inhibitors of the formula(I),

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof, wherein:X¹ is selected from the group consisting of CR^(4a) and N;X² is selected from the group consisting of CR^(4b) and N;X³ is selected from the group consisting of CR^(4c) and N;R¹ is selected from the group consisting of optionally substituted C₁₋₆linear alkyl, optionally substituted C₃₋₆ branched alkyl, optionallysubstituted C₃₋₆ cyclic alkyl, optionally substituted phenyl, optionallysubstituted heteroaryl, optionally substituted benzyl, optionallysubstituted heteroaryl methyl,

R² is selected from the group consisting of hydrogen, NR^(10a)R^(10b),fluorine, optionally substituted phenyl, optionally substitutedheteroaryl,

R³ is selected from the group consisting of CO₂R^(4d),

R^(4a), R^(4b), and R^(4c) are each independently selected from thegroup consisting of fluorine, chlorine, bromine, iodine, and hydrogen;R^(4d) is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R^(8a), R^(8b), R^(8c), R^(8d), and R^(8e) are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branched alkyl;R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branched alkyl;R^(10a), and R^(10b) are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ linear alkyl, andoptionally substituted C₁₋₆ branched alkyl;L¹ is selected from the group consisting of

and (CH₂)_(n);L² is selected from a group consisting of NH, (CH₂)_(m), and

wherein “**” indicates the point of attachment for R²;n is 0, 1, 2, or 3; andm is 0, 1, 2, or 3.

The compounds of the present invention include compounds having formula(II):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof. Substituents for this formulaand subsequent formulas are as noted above for formula (I), unlessotherwise specified.

The compounds of the present invention include compounds having formula(III):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(IV):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(V):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(VII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(VIII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(IX):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(X):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XI):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XIII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XIV):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XV):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XVI):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XVII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The present invention further relates to compositions comprising aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing diseases or conditions caused by EBNA1 activity, the methodcomprising administering to a subject an effective amount of a compoundor composition according to the present invention.

The present invention yet further relates to a method for treating orpreventing diseases or conditions caused by EBNA1 activity, wherein themethod comprises administering to a subject a composition comprising aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to methods for treating or preventingdisease or conditions associated with EBNA1 activity. The methodscomprise administering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with EBNA1 activity, whereinthe method comprises administering to a subject a composition comprisingan effective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing EBV infection, the method comprising administering to asubject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating orpreventing EBV infection, wherein the method comprises administering toa subject a composition comprising an effective amount of one or morecompounds according to the present invention and an excipient.

The present invention also relates to methods for treating or preventingdisease or conditions associated with EBV infection. The methodscomprise administering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with EBV infection, whereinthe method comprises administering to a subject a composition comprisingan effective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing lytic EBV infection, the method comprising administering to asubject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating orpreventing lytic EBV infection, wherein the method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention also relates to methods for treating or preventingdisease or conditions associated with lytic EBV infection. The methodscomprise administering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with lytic EBV infection,wherein the method comprises administering to a subject a compositioncomprising an effective amount of one or more compounds according to thepresent invention and an excipient.

The present invention also relates to a method for treating orpreventing latent EBV infection, the method comprising administering toa subject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating orpreventing latent EBV infection, wherein the method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention also relates to methods for treating or preventingdisease or conditions associated with latent EBV infection. The methodscomprise administering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with latent EBV infection,wherein the method comprises administering to a subject a compositioncomprising an effective amount of one or more compounds according to thepresent invention and an excipient.

The present invention yet further relates to a method for treating orpreventing cancer, particularly nasopharyngeal carcinoma, gastriccarcinomas, non-Hodgkin lymphoma, anaplastic large-cell lymphoma,angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma,B-cell lymphoma, Burkitt's lymphoma, reticuloendotheliosis, reticulosis,microglioma, diffuse large B-cell lymphoma, extranodal T/NKlymphoma/angiocentric lymphoma, follicular lymphoma, immunoblasticlymphoma, mucosa-associated lymphatic tissue lymphoma, B-cell chroniclymphocytic leukemia, mantle cell lymphoma, mediastinal large B celllymphoma, lymphoplasmactic lymphoma, nodal marginal zone B celllymphoma, splenic marginal zone lymphoma, intravascular large B-celllymphoma, primary effusion lymphoma, lyphomatoid granulomatosis,angioimmunoblastic lymphadenopathy, leiomyosarcomas, X-linkedlymphoproliferative disease, post-transplant lymphoproliferativedisorders, Hodgkin's lymphoma and breast cancer.

The present invention yet further relates to a method for treating ofpreventing cancer, particularly nasopharyngeal carcinoma, gastriccarcinomas, non-hodgkin lymphoma, anaplastic large-cell lymphoma,angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma,B-cell lymphoma, Burkitt's lymphoma, reticuloendotheliosis, reticulosis,microglioma, diffuse large B-cell lymphoma, extranodal T/NKlymphoma/angiocentric lymphoma, follicular lymphoma, immunoblasticlymphoma, mucosa-associated lymphatic tissue lymphoma, B-cell chroniclymphocytic leukemia, mantle cell lymphoma, mediastinal large B celllymphoma, lymphoplasmactic lymphoma, nodal marginal zone B celllymphoma, splenic marginal zone lymphoma, intravascular large B-celllymphoma, primary effusion lymphoma, lyphomatoid granulomatosis,angioimmunoblastic lymphadenopathy, leiomyosarcomas, X-linkedlymphoproliferative disease, post-transplant lymphoproliferativedisorders, Hodgkin's lymphoma and breast cancer wherein the methodcomprising administering to a subject an effective amount of a compoundor composition according to the present invention.

The present invention yet further relates to a method for treating ofpreventing cancer particularly nasopharyngeal carcinoma, gastriccarcinomas, non-hodgkin lymphoma, anaplastic large-cell lymphoma,angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma,B-cell lymphoma, Burkitt's lymphoma, reticuloendotheliosis, reticulosis,microglioma, diffuse large B-cell lymphoma, extranodal T/NKlymphoma/angiocentric lymphoma, follicular lymphoma, immunoblasticlymphoma, mucosa-associated lymphatic tissue lymphoma, B-cell chroniclymphocytic leukemia, mantle cell lymphoma, mediastinal large B celllymphoma, lymphoplasmactic lymphoma, nodal marginal zone B celllymphoma, splenic marginal zone lymphoma, intravascular large B-celllymphoma, primary effusion lymphoma, lyphomatoid granulomatosis,angioimmunoblastic lymphadenopathy, leiomyosarcomas, X-linkedlymphoproliferative disease, post-transplant lymphoproliferativedisorders, Hodgkin's lymphoma and breast cancer wherein the methodcomprising administering to a subject an effective amount of a compoundor composition according to the present invention and an excipient.

The present invention yet further relates to a method for treating orpreventing infectious mononucleosis.

The present invention yet further relates to a method for treating ofinfectious mononucleosis wherein the method comprising administering toa subject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating ofpreventing infectious mononucleosis wherein the method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention and an excipient.

The present invention yet further relates to a method for treating orpreventing chronic fatigue syndrome.

The present invention yet further relates to a method for treating ofchronic fatigue syndrome wherein the method comprising administering toa subject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating ofpreventing chronic fatigue syndrome wherein the method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention and an excipient.

The present invention yet further relates to a method for treating orpreventing multiple sclerosis.

The present invention yet further relates to a method for treating ofmultiple sclerosis wherein the method comprising administering to asubject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating ofpreventing multiple sclerosis wherein the method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention and an excipient.

The present invention yet further relates to a method for treating orpreventing systemic lupus erythematosus.

The present invention yet further relates to a method for treating ofsystemic lupus erythematosus wherein the method comprising administeringto a subject an effective amount of a compound or composition accordingto the present invention.

The present invention yet further relates to a method for treating ofpreventing systemic lupus erythematosus wherein the method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention and an excipient.

The present invention yet further relates to a method for treating orpreventing rheumatoid arthritis.

The present invention yet further relates to a method for treating ofrheumatoid arthritis wherein the method comprising administering to asubject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating ofpreventing rheumatoid arthritis wherein the method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention and an excipient.

The present invention further relates to a process for preparing theEBNA1-inhibitors of the present invention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The EBNA1-inhibitors of the present invention are capable of treatingand preventing diseases or conditions caused by EBNA1 activity. Inaddition, compounds of the disclosure are capable of treating andpreventing disease or conditions associated with EBNA1 activity.Further, compounds of the disclosure are also capable of treating orpreventing EBV infection. In addition, compounds of the disclosure arecapable of treating or preventing disease or conditions associated withEBV infection. Further, compounds of the disclosure are also capable oftreating or preventing lytic EBV infection. Compounds of the disclosureare also capable of treating or preventing latent EBV infection. Inaddition, compounds of the disclosure are also capable of treating orpreventing disease or conditions associated with lytic EBV infection.Further, compounds of the disclosure are also capable of treating orpreventing disease or conditions associated with latent EBV infection.Without wishing to be limited by theory, it is believed that theEBNA1-inhibitors of the present invention can ameliorate, abate,prevent, reverse, or otherwise cause to be controlled, cancer,particularly nasopharyngeal carcinoma, gastric carcinomas, non-hodgkinlymphoma, anaplastic large-cell lymphoma, angioimmunoblastic T-celllymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt'slymphoma, reticuloendotheliosis, reticulosis, microglioma, diffuse largeB-cell lymphoma, extranodal T/NK lymphoma/angiocentric lymphoma,follicular lymphoma, immunoblastic lymphoma, mucosa-associated lymphatictissue lymphoma, B-cell chronic lymphocytic leukemia, mantle celllymphoma, mediastinal large B cell lymphoma, lymphoplasmactic lymphoma,nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma,intravascular large B-cell lymphoma, primary effusion lymphoma,lyphomatoid granulomatosis, angioimmunoblastic lymphadenopathy,leiomyosarcomas, X-linked lymphoproliferative disease, post-transplantlymphoproliferative disorders, Hodgkin's lymphoma and breast cancer.Further, without wishing to be limited by theory, it is believed thatthe EBNA1-inhibitors of the present invention can ameliorate, abate,prevent, reverse, or otherwise cause to be controlled infectiousmononucleosis. Further, without wishing to be limited by theory, it isbelieved that the EBNA1-inhibitors of the present invention canameliorate, abate, prevent, reverse, or otherwise cause to be controlledinfectious mononucleosis. Further, without wishing to be limited bytheory, it is believed that the EBNA1-inhibitors of the presentinvention can ameliorate, abate, prevent, reverse, or otherwise cause tobe controlled chronic fatigue syndrome. Further, without wishing to belimited by theory, it is believed that the EBNA1-inhibitors of thepresent invention can ameliorate, abate, prevent, reverse, or otherwisecause to be controlled multiple sclerosis. In addition, without wishingto be limited by theory, it is believed that the EBNA1-inhibitors of thepresent invention can ameliorate, abate, prevent, reverse, or otherwisecause to be controlled systemic lupus erythematosus. In addition,without wishing to be limited by theory, it is believed that theEBNA1-inhibitors of the present invention can ameliorate, abate,prevent, reverse, or otherwise cause to be controlled and rheumatoidarthritis.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from a groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously.

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and “aliphatic” whetherused alone or as part of a substituent group refers to straight andbranched carbon chains having 1 to 20 carbon atoms or any number withinthis range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms.Designated numbers of carbon atoms (e.g. C₁₋₆) shall refer independentlyto the number of carbon atoms in an alkyl moiety or to the alkyl portionof a larger alkyl-containing substituent. Non-limiting examples of alkylgroups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, and the like. Alkyl groups can be optionallysubstituted. Non-limiting examples of substituted alkyl groups includehydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl,1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, andthe like. In substituent groups with multiple alkyl groups such as(C₁₋₆alkyl)₂ amino, the alkyl groups may be the same or different.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused,bridged, and/or spiro ring systems), wherein the carbon atoms arelocated inside or outside of the ring system. Any suitable ring positionof the cycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens of an alkyl grouphave been replaced with halogens (e.g., —CF₃, CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substituents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atomsand at least one oxygen atom (e.g., tetrahydrofuran,tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may besubstituted.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, wherethe alkyl and aryl groups are as defined herein. Aralkyl groups of thepresent invention are optionally substituted. Examples of arylalkylgroups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrrolyl,thiophenyl, furanyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyloxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl,pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl,tetrahydropyranyl, piperidin-2-onyl (valerolactam),2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and1,2,3,4-tetrahydroquinoline. Non-limiting examples of heterocyclic unitshaving 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. Heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,benzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, and isoquinolinyl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposes of the present invention, fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms of asingle moiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. The term “substituted” is used throughout thepresent specification to indicate that a moiety can have one or more ofthe hydrogen atoms replaced by a substituent. When a moiety is describedas “substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, cycloalkyl, alkoxy,aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whetherused alone or as part of another group, can be optionally substituted.Optionally substituted groups will be so indicated.

The following are non-limiting examples of substituents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine(I)), —CN, —NO₂, oxo (═O), —OR¹⁰,—SR¹⁰, —N(R¹⁰)₂, —NR¹⁰C(O)R¹⁰, —SO₂R¹⁰, —SO₂OR¹⁰, —SO₂N(R¹⁰)₂, —C(O)R¹⁰,—C(O)OR¹⁰, —C(O)N(R¹⁰)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R¹⁰; wherein R¹⁰, ateach occurrence, independently is hydrogen, —OR¹¹, —SR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —C(O)N(R¹¹)₂, —SO₂R¹¹, —S(O)₂OR¹¹, —N(R¹¹)₂, NR¹¹C(O)R¹¹,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl(e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R¹⁰units taken together with the atom(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R¹¹, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R^(H) units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

i) —OR¹²; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;

ii) —C(O)R¹²; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;

iii) —C(O)OR¹²; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;

iv) —C(O)N(R¹²)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;

v) —N(R¹²)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);

vi) halogen: —F, —Cl, —Br, and —I;

vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2, e+g=3; forexample, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;

viii) —SO₂R¹²; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;

ix) C₁-C₆ linear, branched, or cyclic alkyl;

x) Cyano

xi) Nitro;

xii) N(R¹²)C(O)R¹²;

xiii) Oxo (═O);

xiv) Heterocycle; and

xv) Heteroaryl.

wherein each R¹² is independently hydrogen, optionally substituted C₁-C₆linear or branched alkyl (e.g., optionally substituted C₁-C₄ linear orbranched alkyl), or optionally substituted C₃-C₆ cycloalkyl (e.goptionally substituted C₃-C₄ cycloalkyl); or two R¹² units can be takentogether to form a ring comprising 3-7 ring atoms. In certain aspects,each R¹² is independently hydrogen, C₁-C₆ linear or branched alkyloptionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆cycloalkyl.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually discloseC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for the prodrugagent described herein, including all enantiomeric forms, diastereomericforms, salts, and the like, and the terms “compound,” “analog,” and“composition of matter” are used interchangeably throughout the presentspecification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄,Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, whena compound disclosed herein contains a basic moiety, salts can be formedusing organic and inorganic acids. For example, salts can be formed fromthe following acids: acetic, propionic, lactic, benzenesulfonic,benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic,ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic,mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic,pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R¹⁰)₂, each R¹⁰ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The terms “treat” and “treating” and “treatment” as used herein, referto partially or completely alleviating, inhibiting, ameliorating and/orrelieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

As used herein, the term “EBNA1 inhibitor” shall mean a compound thatinhibits EBNA1.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention.

The EBNA1 Inhibitors:

The EBNA1 inhibitors of the present invention include all enantiomericand diastereomeric forms and pharmaceutically accepted salts thereofhaving the formula (I):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof, wherein:X¹ is selected from the group consisting of CR^(4a) and N;X² is selected from the group consisting of CR^(4b) and N;X³ is selected from the group consisting of CR^(4c) and N;R¹ is selected from the group consisting of optionally substituted C₁₋₆linear alkyl, optionally substituted C₃₋₆ branched alkyl, optionallysubstituted C₃₋₆ cyclic alkyl, optionally substituted phenyl, optionallysubstituted heteroaryl, optionally substituted benzyl, optionallysubstituted heteroaryl methyl,

R² is selected from the group consisting of hydrogen, NR^(10a)R^(10b),fluorine, optionally substituted phenyl, optionally substitutedheteroaryl,

R³ is selected from the group consisting of CO₂R^(4d),

R^(4a), R^(4b), and R^(4c) are each independently selected from thegroup consisting of fluorine, chlorine, bromine, iodine, and hydrogen;R^(4d) is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R⁵ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R⁶ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R⁷ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branchedalkyl;R^(8a), R^(8b), R^(8c), R^(8d), and R^(8e) are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branched alkyl;R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ linear alkyl, and optionally substituted C₃₋₆ branched alkyl;R^(10a), and R^(10b) are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ linear alkyl, andoptionally substituted C₁₋₆ branched alkyl;L¹ is selected from the group consisting of

and (CH₂)_(n);L² is selected from a group consisting of NH, (CH₂)_(m), and

wherein “**” indicates the point of attachment for R²;n is 0, 1, 2, or 3; andm is 0, 1, 2, or 3.

The compounds of the present invention include compounds having formula(II):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof. Substituents for this formulaand subsequent formulas are as noted above for formula (I), unlessotherwise specified.

The compounds of the present invention include compounds having formula(III):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(IV):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(V):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(VI):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(VII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(VIII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(IX):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(X):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XI):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XIII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XIV):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XV):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XVI):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

The compounds of the present invention include compounds having formula(XVII):

including hydrates, solvates, polymorphs, pharmaceutically acceptablesalts, prodrugs, and complexes thereof.

In some embodiments X¹ is CR^(4a).

In some embodiments X¹ is N.

In some embodiments X² is CR^(4a).

In some embodiments X² is N.

In some embodiments X³ is CR^(4a).

In some embodiments X³ is N.

In some embodiments R¹ is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R¹ is optionally substituted C₃₋₆ branched alkyl.

In some embodiments R¹ is optionally substituted C₃₋₆ cyclic alkyl.

In some embodiments R¹ is optionally substituted heteroaryl methyl.

In some embodiments R¹ is optionally substituted phenyl.

In some embodiments R¹ is optionally substituted heteroaryl.

In some embodiments R¹ is optionally substituted benzyl.

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R¹ is

In some embodiments R² is hydrogen.

In some embodiments R² is NR^(10a)R^(10b).

In some embodiments R² is fluorine.

In some embodiments R² is optionally substituted phenyl.

In some embodiments R² is optionally substituted heteroaryl.

In some embodiments R² is

In some embodiments R² is

In some embodiments R² is

In some embodiments R³ is CO₂R^(4d).

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R^(4a) is fluorine.

In some embodiments R^(4a) is chlorine.

In some embodiments R^(4a) is bromine.

In some embodiments R^(4a) is iodine.

In some embodiments R^(4a) is hydrogen.

In some embodiments R^(4b) is fluorine.

In some embodiments R^(4b) is chlorine.

In some embodiments R^(4b) is bromine.

In some embodiments R^(4b) is iodine.

In some embodiments R^(4b) is hydrogen.

In some embodiments R^(4c) is fluorine.

In some embodiments R^(4c) is chlorine.

In some embodiments R^(4c) is bromine.

In some embodiments R^(4c) is iodine.

In some embodiments R^(4c) is hydrogen.

In some embodiments R^(4d) is hydrogen.

In some embodiments R^(4d) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(4d) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R⁵ is hydrogen.

In some embodiments R⁵ is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R⁵ is optionally substituted C₃₋₆ branched alkyl.

In some embodiments R⁶ is hydrogen.

In some embodiments R⁶ is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R⁶ is optionally substituted C₃₋₆ branched alkyl.

In some embodiments R⁷ is hydrogen.

In some embodiments R⁷ is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R⁷ is optionally substituted C₃₋₆ branched alkyl.

In some embodiments R^(8a) is hydrogen.

In some embodiments R^(8a) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(8a) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(8b) is hydrogen.

In some embodiments R^(8b) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(8b) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(8c) is hydrogen.

In some embodiments R^(8c) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(8c) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(8d) is hydrogen.

In some embodiments R^(8d) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(8d) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(9a) is hydrogen.

In some embodiments R^(9a) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(9a) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(9b) is hydrogen.

In some embodiments R^(9b) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(9b) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(9c) is hydrogen.

In some embodiments R^(9c) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(9c) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(9d) is hydrogen.

In some embodiments R^(9d) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(9d) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(10a) is hydrogen.

In some embodiments R^(10a) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(10a) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments R^(10b) is hydrogen.

In some embodiments R^(10b) is optionally substituted C₁₋₆ linear alkyl.

In some embodiments R^(10b) is optionally substituted C₃₋₆ branchedalkyl.

In some embodiments L¹ is

In some embodiments L¹ is

In some embodiments L¹ is (CH₂)_(n).

In some embodiments L² is NH.

In some embodiments L² is (CH₂)_(m).

In some embodiments L² is

wherein “**” indicates the point of attachment for R².

In some embodiments m is 0.

In some embodiments m is 1.

In some embodiments m is 2.

In some embodiments m is 3.

In some embodiments n is 0.

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments n is 3.

Exemplary embodiments include compounds having the formula (XVIII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹, R², and m are defined herein belowin Table 1.

TABLE 1 Entry R¹ R² m 1 phenyl N-pyrrolyl 0 2 2-fluorophenyl N-pyrrolyl0 3 3-fluorophenyl N-pyrrolyl 0 4 4-fluorophenyl N-pyrrolyl 0 52,3-difluorophenyl N-pyrrolyl 0 6 2,4-difluorophenyl N-pyrrolyl 0 73,4-difluorophenyl N-pyrrolyl 0 8 3,5-difluorophenyl N-pyrrolyl 0 92,6-difluorophenyl N-pyrrolyl 0 10 2,4,6-trifluorophenyl N-pyrrolyl 0 112-chlorophenyl N-pyrrolyl 0 12 3-chlorophenyl N-pyrrolyl 0 134-chlorophenyl N-pyrrolyl 0 14 2,3-dichlorophenyl N-pyrrolyl 0 152,4-dichlorophenyl N-pyrrolyl 0 16 3,4-dichlorophenyl N-pyrrolyl 0 173,5-dichlorophenyl N-pyrrolyl 0 18 2,6-dichlorophenyl N-pyrrolyl 0 193-chloro-5-fluorophenyl N-pyrrolyl 0 20 2-hydroxyphenyl N-pyrrolyl 0 213-hydroxyphenyl N-pyrrolyl 0 22 4-hydroxyphenyl N-pyrrolyl 0 233-fluoro-4-hydroxyphenyl N-pyrrolyl 0 24 3-fluoro-5-hydroxyphenylN-pyrrolyl 0 25 3-chloro-4-hydroxyphenyl N-pyrrolyl 0 263-chloro-5-hydroxyphenyl N-pyrrolyl 0 27 2-methoxyphenyl N-pyrrolyl 0 283-methoxyphenyl N-pyrrolyl 0 29 4-methoxyphenyl N-pyrrolyl 0 302-methoxy-4-fluorophenyl N-pyrrolyl 0 31 2-methoxy-5-fluorophenylN-pyrrolyl 0 32 3-methoxy-5-fluorophenyl N-pyrrolyl 0 332-methoxy-4-chlorophenyl N-pyrrolyl 0 34 2-methoxy-5-chlorophenylN-pyrrolyl 0 35 3-methoxy-5-chlorophenyl N-pyrrolyl 0 363-hydroxy-5-methoxyphenyl N-pyrrolyl 0 37 3-carboxamidophenyl N-pyrrolyl0 38 3-carboxamido-4-fluorophenyl N-pyrrolyl 0 393-carboxamido-5-fluorophenyl N-pyrrolyl 0 403-carboxamido-4-hydroxyphenyl N-pyrrolyl 0 413-carboxamido-5-hydroxyphenyl N-pyrrolyl 0 423-carboxamido-4-methoxyphenyl N-pyrrolyl 0 433-carboxamido-5-methoxyphenyl N-pyrrolyl 0 44 4-carboxamidophenylN-pyrrolyl 0 45 3-fluoro-4-carboxamidephenyl N-pyrrolyl 0 463-chloro-4-carboxamidephenyl N-pyrrolyl 0 473-hydroxy-4-carboxamidephenyl N-pyrrolyl 0 483-methoxy-4-carboxamidephenyl N-pyrrolyl 0 49 2-trifluoromethylphenylN-pyrrolyl 0 50 3-trifluoromethylphenyl N-pyrrolyl 0 514-trifluoromethylphenyl N-pyrrolyl 0 52 2-trifluoromethoxyphenylN-pyrrolyl 0 53 3-trifluoromethoxyphenyl N-pyrrolyl 0 544-trifluoromethoxyphenyl N-pyrrolyl 0 55 2-difluoromethoxyphenylN-pyrrolyl 0 56 3-difluoromethoxyphenyl N-pyrrolyl 0 574-difluoromethoxyphenyl N-pyrrolyl 0 58 2-methylphenyl N-pyrrolyl 0 593-methylphenyl N-pyrrolyl 0 60 4-methylphenyl N-pyrrolyl 0 612,4-dimethylphenyl N-pyrrolyl 0 62 3,4-dimethylphenyl N-pyrrolyl 0 633,5-dimethylphenyl N-pyrrolyl 0 64 2-hydroxymethylphenyl N-pyrrolyl 0 653-hydroxymethylphenyl N-pyrrolyl 0 66 3-(2-hydroxyprop-2-yl)phenylN-pyrrolyl 0 67 4-hydroxymethylphenyl N-pyrrolyl 0 68 2-carboxyphenylN-pyrrolyl 0 69 3-carboxyphenyl N-pyrrolyl 0 70 4-carboxyphenylN-pyrrolyl 0 71 3-aminomethylphenyl N-pyrrolyl 0 72 4-aminomethylphenylN-pyrrolyl 0 73 3-cyclopropanesulfonamidomethylphenyl N-pyrrolyl 0 743-benzenesulfonamidomethyl N-pyrrolyl 0 75 3-(3,5-difluoro- N-pyrrolyl 0benzenesulfonamidomethyl)phenyl 76 4-cyclopropanesulfonamidomethylphenylN-pyrrolyl 0 77 4-benzenesulfonamidomethylphenyl N-pyrrolyl 0 784-(3,5-difluoro- N-pyrrolyl 0 benzenesulfonamidomethyl)phenyl 794-(1,2-dimethyl-1H-imidazole-5- N-pyrrolyl 0 sulfonamidomethyl)phenyl 803-dimethylsulfamoylphenyl N-pyrrolyl 0 81 3-methylsulfamoylphenylN-pyrrolyl 0 82 3-sulfamoylphenyl N-pyrrolyl 0 833-methanesulfonamidophenyl N-pyrrolyl 0 84 4-dimethylsulfamoylphenylN-pyrrolyl 0 85 4-methylsulfamoylphenyl N-pyrrolyl 0 864-sulfamoylphenyl N-pyrrolyl 0 87 4-methanesulfonamidophenyl N-pyrrolyl0 88 3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl N-pyrrolyl 0 893-[(2-carboxy-2,2-dimethylethyl)amino]phenyl N-pyrrolyl 0 904-acetylamidophenyl N-pyrrolyl 0 91 3-acetylamidophenyl N-pyrrolyl 0 92phenyl 1H-indol-5-yl 0 93 2-fluorophenyl 1H-indol-5-yl 0 943-fluorophenyl 1H-indol-5-yl 0 95 4-fluorophenyl 1H-indol-5-yl 0 962,3-difluorophenyl 1H-indol-5-yl 0 97 2,4-difluorophenyl 1H-indol-5-yl 098 3,4-difluorophenyl 1H-indol-5-yl 0 99 3,5-difluorophenyl1H-indol-5-yl 0 100 2,6-difluorophenyl 1H-indol-5-yl 0 1012,4,6-trifluorophenyl 1H-indol-5-yl 0 102 2-chlorophenyl 1H-indol-5-yl 0103 3-chlorophenyl 1H-indol-5-yl 0 104 4-chlorophenyl 1H-indol-5-yl 0105 2,3-dichlorophenyl 1H-indol-5-yl 0 106 2,4-dichlorophenyl1H-indol-5-yl 0 107 3,4-dichlorophenyl 1H-indol-5-yl 0 1083,5-dichlorophenyl 1H-indol-5-yl 0 109 2,6-dichlorophenyl 1H-indol-5-yl0 110 3-chloro-5-fluorophenyl 1H-indol-5-yl 0 111 2-hydroxyphenyl1H-indol-5-yl 0 112 3-hydroxyphenyl 1H-indol-5-yl 0 113 4-hydroxyphenyl1H-indol-5-yl 0 114 3-fluoro-4-hydroxyphenyl 1H-indol-5-yl 0 1153-fluoro-5-hydroxyphenyl 1H-indol-5-yl 0 116 3-chloro-4-hydroxyphenyl1H-indol-5-yl 0 117 3-chloro-5-hydroxyphenyl 1H-indol-5-yl 0 1182-methoxyphenyl 1H-indol-5-yl 0 119 3-methoxyphenyl 1H-indol-5-yl 0 1204-methoxyphenyl 1H-indol-5-yl 0 121 2-methoxy-4-fluorophenyl1H-indol-5-yl 0 122 2-methoxy-5-fluorophenyl 1H-indol-5-yl 0 1233-methoxy-5-fluorophenyl 1H-indol-5-yl 0 124 2-methoxy-4-chlorophenyl1H-indol-5-yl 0 125 2-methoxy-5-chlorophenyl 1H-indol-5-yl 0 1263-methoxy-5-chlorophenyl 1H-indol-5-yl 0 127 3-hydroxy-5-methoxyphenyl1H-indol-5-yl 0 128 3-carboxamidophenyl 1H-indol-5-yl 0 1293-carboxamido-4-fluorophenyl 1H-indol-5-yl 0 1303-carboxamido-5-fluorophenyl 1H-indol-5-yl 0 1313-carboxamido-4-hydroxyphenyl 1H-indol-5-yl 0 1323-carboxamido-5-hydroxyphenyl 1H-indol-5-yl 0 1333-carboxamido-4-methoxyphenyl 1H-indol-5-yl 0 1343-carboxamido-5-methoxyphenyl 1H-indol-5-yl 0 135 4-carboxamidophenyl1H-indol-5-yl 0 136 3-fluoro-4-carboxamidephenyl 1H-indol-5-yl 0 1373-chloro-4-carboxamidephenyl 1H-indol-5-yl 0 1383-hydroxy-4-carboxamidephenyl 1H-indol-5-yl 0 1393-methoxy-4-carboxamidephenyl 1H-indol-5-yl 0 1402-trifluoromethylphenyl 1H-indol-5-yl 0 141 3-trifluoromethylphenyl1H-indol-5-yl 0 142 4-trifluoromethylphenyl 1H-indol-5-yl 0 1432-trifluoromethoxyphenyl 1H-indol-5-yl 0 144 3-trifluoromethoxyphenyl1H-indol-5-yl 0 145 4-trifluoromethoxyphenyl 1H-indol-5-yl 0 1462-difluoromethoxyphenyl 1H-indol-5-yl 0 147 3-difluoromethoxyphenyl1H-indol-5-yl 0 148 4-difluoromethoxyphenyl 1H-indol-5-yl 0 1492-methylphenyl 1H-indol-5-yl 0 150 3-methylphenyl 1H-indol-5-yl 0 1514-methylphenyl 1H-indol-5-yl 0 152 2,4-dimethylphenyl 1H-indol-5-yl 0153 3,4-dimethylphenyl 1H-indol-5-yl 0 154 3,5-dimethylphenyl1H-indol-5-yl 0 155 2-hydroxymethylphenyl 1H-indol-5-yl 0 1563-hydroxymethylphenyl 1H-indol-5-yl 0 157 3-(2-hydroxyprop-2-yl)phenyl1H-indol-5-yl 0 158 4-hydroxymethylphenyl 1H-indol-5-yl 0 1592-carboxyphenyl 1H-indol-5-yl 0 160 3-carboxyphenyl 1H-indol-5-yl 0 1614-carboxyphenyl 1H-indol-5-yl 0 162 3-aminomethylphenyl 1H-indol-5-yl 0163 4-aminomethylphenyl 1H-indol-5-yl 0 1643-cyclopropanesulfonamidomethylphenyl 1H-indol-5-yl 0 1653-benzenesulfonamidomethylphenyl 1H-indol-5-yl 0 166 3-(3,5-difluoro-1H-indol-5-yl 0 benzenesulfonamidomethyl)phenyl 1674-cyclopropanesulfonamidomethylphenyl 1H-indol-5-yl 0 1684-benzenesulfonamidomethylphenyl 1H-indol-5-yl 0 169 4-(3,5-difluoro-1H-indol-5-yl 0 benzenesulfonamidomethyl)phenyl 1704-(1,2-dimethyl-1H-imidazole-5- 1H-indol-5-yl 0 sulfonamidomethyl)phenyl171 3-dimethylsulfamoylphenyl 1H-indol-5-yl 0 1723-methylsulfamoylphenyl 1H-indol-5-yl 0 173 3-sulfamoylphenyl1H-indol-5-yl 0 174 3-methanesulfonamidophenyl 1H-indol-5-yl 0 1754-dimethylsulfamoylphenyl 1H-indol-5-yl 0 176 4-methylsulfamoylphenyl1H-indol-5-yl 0 177 4-sulfamoylphenyl 1H-indol-5-yl 0 1784-methanesulfonamidophenyl 1H-indol-5-yl 0 1793-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl 1H-indol-5-yl 0 1803-[(2-carboxy-2,2-dimethylethyl)amino]phenyl 1H-indol-5-yl 1814-acetylamidophenyl 1H-indol-5-yl 0 182 3-acetylamidophenyl1H-indol-5-yl 0 183 phenyl 3-hydroxyphenyl 0 184 2-fluorophenyl3-hydroxyphenyl 0 185 3-fluorophenyl 3-hydroxyphenyl 0 1864-fluorophenyl 3-hydroxyphenyl 0 187 2,3-difluorophenyl 3-hydroxyphenyl0 188 2,4-difluorophenyl 3-hydroxyphenyl 0 189 3,4-difluorophenyl3-hydroxyphenyl 0 190 3,5-difluorophenyl 3-hydroxyphenyl 0 1912,6-difluorophenyl 3-hydroxyphenyl 0 192 2,4,6-trifluorophenyl3-hydroxyphenyl 0 193 2-chlorophenyl 3-hydroxyphenyl 0 1943-chlorophenyl 3-hydroxyphenyl 0 195 4-chlorophenyl 3-hydroxyphenyl 0196 2,3-dichlorophenyl 3-hydroxyphenyl 0 197 2,4-dichlorophenyl3-hydroxyphenyl 0 198 3,4-dichlorophenyl 3-hydroxyphenyl 0 1993,5-dichlorophenyl 3-hydroxyphenyl 0 200 2,6-dichlorophenyl3-hydroxyphenyl 0 201 3-chloro-5-fluorophenyl 3-hydroxyphenyl 0 2022-hydroxyphenyl 3-hydroxyphenyl 0 203 3-hydroxyphenyl 3-hydroxyphenyl 0204 4-hydroxyphenyl 3-hydroxyphenyl 0 205 3-fluoro-4-hydroxyphenyl3-hydroxyphenyl 0 206 3-fluoro-5-hydroxyphenyl 3-hydroxyphenyl 0 2073-chloro-4-hydroxyphenyl 3-hydroxyphenyl 0 208 3-chloro-5-hydroxyphenyl3-hydroxyphenyl 0 209 2-methoxyphenyl 3-hydroxyphenyl 0 2103-methoxyphenyl 3-hydroxyphenyl 0 211 4-methoxyphenyl 3-hydroxyphenyl 0212 2-methoxy-4-fluorophenyl 3-hydroxyphenyl 0 2132-methoxy-5-fluorophenyl 3-hydroxyphenyl 0 214 3-methoxy-5-fluorophenyl3-hydroxyphenyl 0 215 2-methoxy-4-chlorophenyl 3-hydroxyphenyl 0 2162-methoxy-5-chlorophenyl 3-hydroxyphenyl 0 217 3-methoxy-5-chlorophenyl3-hydroxyphenyl 0 218 3-hydroxy-5-methoxyphenyl 3-hydroxyphenyl 0 2193-carboxamidophenyl 3-hydroxyphenyl 0 220 3-carboxamido-4-fluorophenyl3-hydroxyphenyl 0 221 3-carboxamido-5-fluorophenyl 3-hydroxyphenyl 0 2223-carboxamido-4-hydroxyphenyl 3-hydroxyphenyl 0 2233-carboxamido-5-hydroxyphenyl 3-hydroxyphenyl 0 2243-carboxamido-4-methoxyphenyl 3-hydroxyphenyl 0 2253-carboxamido-5-methoxyphenyl 3-hydroxyphenyl 0 226 4-carboxamidophenyl3-hydroxyphenyl 0 227 3-fluoro-4-carboxamidephenyl 3-hydroxyphenyl 0 2283-chloro-4-carboxamidephenyl 3-hydroxyphenyl 0 2293-hydroxy-4-carboxamidephenyl 3-hydroxyphenyl 0 2303-methoxy-4-carboxamidephenyl 3-hydroxyphenyl 0 2312-trifluoromethylphenyl 3-hydroxyphenyl 0 232 3-trifluoromethylphenyl3-hydroxyphenyl 0 233 4-trifluoromethylphenyl 3-hydroxyphenyl 0 2342-trifluoromethoxyphenyl 3-hydroxyphenyl 0 235 3-trifluoromethoxyphenyl3-hydroxyphenyl 0 236 4-trifluoromethoxyphenyl 3-hydroxyphenyl 0 2372-difluoromethoxyphenyl 3-hydroxyphenyl 0 238 3-difluoromethoxyphenyl3-hydroxyphenyl 0 239 4-difluoromethoxyphenyl 3-hydroxyphenyl 0 2402-methylphenyl 3-hydroxyphenyl 0 241 3-methylphenyl 3-hydroxyphenyl 0242 4-methylphenyl 3-hydroxyphenyl 0 243 2,4-dimethylphenyl3-hydroxyphenyl 0 244 3,4-dimethylphenyl 3-hydroxyphenyl 0 2453,5-dimethylphenyl 3-hydroxyphenyl 0 246 2-hydroxymethylphenyl3-hydroxyphenyl 0 247 3-hydroxymethylphenyl 3-hydroxyphenyl 0 2483-(2-hydroxyprop-2-yl)phenyl 3-hydroxyphenyl 0 249 4-hydroxymethylphenyl3-hydroxyphenyl 0 250 2-carboxyphenyl 3-hydroxyphenyl 0 2513-carboxyphenyl 3-hydroxyphenyl 0 252 4-carboxyphenyl 3-hydroxyphenyl 0253 3-aminomethylphenyl 3-hydroxyphenyl 0 254 4-aminomethylphenyl3-hydroxyphenyl 0 255 3-cyclopropanesulfonamidomethylphenyl3-hydroxyphenyl 0 256 3-benzenesulfonamidomethylphenyl 3-hydroxyphenyl 0257 3-(3,5-difluoro- 3-hydroxyphenyl 0 benzenesulfonamidomethyl)phenyl258 4-cyclopropanesulfonamidomethylphenyl 3-hydroxyphenyl 0 2594-benzenesulfonamidomethylphenyl 3-hydroxyphenyl 0 260 4-(3,5-difluoro-3-hydroxyphenyl 0 benzenesulfonamidomethyl)phenyl 2614-(1,2-dimethyl-1H-imidazole-5- 3-hydroxyphenyl 0sulfonamidomethyl)phenyl 262 3-dimethylsulfamoylphenyl 3-hydroxyphenyl 0263 3-methylsulfamoylphenyl 3-hydroxyphenyl 0 264 3-sulfamoylphenyl3-hydroxyphenyl 0 265 3-methanesulfonamidophenyl 3-hydroxyphenyl 0 2664-dimethylsulfamoylphenyl 3-hydroxyphenyl 0 267 4-methylsulfamoylphenyl3-hydroxyphenyl 0 268 4-sulfamoylphenyl 3-hydroxyphenyl 0 2694-methanesulfonamidophenyl 3-hydroxyphenyl 0 2703-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl 3-hydroxyphenyl 0 2713-[(2-carboxy-2,2-dimethylethyl)amino]phenyl 3-hydroxyphenyl 2724-acetylamidophenyl 3-hydroxyphenyl 0 273 3-acetylamidophenyl3-hydroxyphenyl 0 274 phenyl F 0 275 2-fluorophenyl F 0 2763-fluorophenyl F 0 277 4-fluorophenyl F 0 278 2,3-difluorophenyl F 0 2792,4-difluorophenyl F 0 280 3,4-difluorophenyl F 0 281 3,5-difluorophenylF 0 282 2,6-difluorophenyl F 0 283 2,4,6-trifluorophenyl F 0 2842-chlorophenyl F 0 285 3-chlorophenyl F 0 286 4-chlorophenyl F 0 2872,3-dichlorophenyl F 0 288 2,4-dichlorophenyl F 0 289 3,4-dichlorophenylF 0 290 3,5-dichlorophenyl F 0 291 2,6-dichlorophenyl F 0 2923-chloro-5-fluorophenyl F 0 293 2-hydroxyphenyl F 0 294 3-hydroxyphenylF 0 295 4-hydroxyphenyl F 0 296 3-fluoro-4-hydroxyphenyl F 0 2973-fluoro-5-hydroxyphenyl F 0 298 3-chloro-4-hydroxyphenyl F 0 2993-chloro-5-hydroxyphenyl F 0 300 2-methoxyphenyl F 0 301 3-methoxyphenylF 0 302 4-methoxyphenyl F 0 303 2-methoxy-4-fluorophenyl F 0 3042-methoxy-5-fluorophenyl F 0 305 3-methoxy-5-fluorophenyl F 0 3062-methoxy-4-chlorophenyl F 0 307 2-methoxy-5-chlorophenyl F 0 3083-methoxy-5-chlorophenyl F 0 309 3-hydroxy-5-methoxyphenyl F 0 3103-carboxamidophenyl F 0 311 3-carboxamido-4-fluorophenyl F 0 3123-carboxamido-5-fluorophenyl F 0 313 3-carboxamido-4-hydroxyphenyl F 0314 3-carboxamido-5-hydroxyphenyl F 0 315 3-carboxamido-4-methoxyphenylF 0 316 3-carboxamido-5-methoxyphenyl F 0 317 4-carboxamidophenyl F 0318 3-fluoro-4-carboxamidephenyl F 0 319 3-chloro-4-carboxamidephenyl F0 320 3-hydroxy-4-carboxamidephenyl F 0 3213-methoxy-4-carboxamidephenyl F 0 322 2-trifluoromethylphenyl F 0 3233-trifluoromethylphenyl F 0 324 4-trifluoromethylphenyl F 0 3252-trifluoromethoxyphenyl F 0 326 3-trifluoromethoxyphenyl F 0 3274-trifluoromethoxyphenyl F 0 328 2-difluoromethoxyphenyl F 0 3293-difluoromethoxyphenyl F 0 330 4-difluoromethoxyphenyl F 0 3312-methylphenyl F 0 332 3-methylphenyl F 0 333 4-methylphenyl F 0 3342,4-dimethylphenyl F 0 335 3,4-dimethylphenyl F 0 336 3,5-dimethylphenylF 0 337 2-hydroxymethylphenyl F 0 338 3-hydroxymethylphenyl F 0 3393-(2-hydroxyprop-2-yl)phenyl F 0 340 4-hydroxymethylphenyl F 0 3412-carboxyphenyl F 0 342 3-carboxyphenyl F 0 343 4-carboxyphenyl F 0 3443-aminomethylphenyl F 0 345 4-aminomethylphenyl F 0 3463-cyclopropanesulfonamidomethylphenyl F 0 347 3-benzenesulfonamidomethylF 0 348 3-(3,5-difluoro- F 0 benzenesulfonamidomethyl)phenyl 3494-cyclopropanesulfonamidomethylphenyl F 0 3504-benzenesulfonamidomethylphenyl F 0 351 4-(3,5-difluoro- F 0benzenesulfonamidomethyl)phenyl 352 4-(1,2-dimethyl-1H-imidazole-5- F 0sulfonamidomethyl)phenyl 353 3-dimethylsulfamoylphenyl F 0 3543-methylsulfamoylphenyl F 0 355 3-sulfamoylphenyl F 0 3563-methanesulfonamidophenyl F 0 357 4-dimethylsulfamoylphenyl F 0 3584-methylsulfamoylphenyl F 0 359 4-sulfamoylphenyl F 0 3604-methanesulfonamidophenyl F 0 3613-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl F 0 3623-[(2-carboxy-2,2-dimethylethyl)amino]phenyl F 0 363 4-acetylamidophenylF 0 364 3-acetylamidophenyl F 0 365 phenyl NH₂ 0 366 2-fluorophenyl NH₂0 367 3-fluorophenyl NH₂ 0 368 4-fluorophenyl NH₂ 0 3692,3-difluorophenyl NH₂ 0 370 2,4-difluorophenyl NH₂ 0 3713,4-difluorophenyl NH₂ 0 372 3,5-difluorophenyl NH₂ 0 3732,6-difluorophenyl NH₂ 0 374 2,4,6-trifluorophenyl NH₂ 0 3752-chlorophenyl NH₂ 0 376 3-chlorophenyl NH₂ 0 377 4-chlorophenyl NH₂ 0378 2,3-dichlorophenyl NH₂ 0 379 2,4-dichlorophenyl NH₂ 0 3803,4-dichlorophenyl NH₂ 0 381 3,5-dichlorophenyl NH₂ 0 3822,6-dichlorophenyl NH₂ 0 383 3-chloro-5-fluorophenyl NH₂ 0 3842-hydroxyphenyl NH₂ 0 385 3-hydroxyphenyl NH₂ 0 386 4-hydroxyphenyl NH₂0 387 3-fluoro-4-hydroxyphenyl NH₂ 0 388 3-fluoro-5-hydroxyphenyl NH₂ 0389 3-chloro-4-hydroxyphenyl NH₂ 0 390 3-chloro-5-hydroxyphenyl NH₂ 0391 2-methoxyphenyl NH₂ 0 392 3-methoxyphenyl NH₂ 0 393 4-methoxyphenylNH₂ 0 394 2-methoxy-4-fluorophenyl NH₂ 0 395 2-methoxy-5-fluorophenylNH₂ 0 396 3-methoxy-5-fluorophenyl NH₂ 0 397 2-methoxy-4-chlorophenylNH₂ 0 398 2-methoxy-5-chlorophenyl NH₂ 0 399 3-methoxy-5-chlorophenylNH₂ 0 400 3-hydroxy-5-methoxyphenyl NH₂ 0 401 3-carboxamidophenyl NH₂ 0402 3-carboxamido-4-fluorophenyl NH₂ 0 403 3-carboxamido-5-fluorophenylNH₂ 0 404 3-carboxamido-4-hydroxyphenyl NH₂ 0 4053-carboxamido-5-hydroxyphenyl NH₂ 0 406 3-carboxamido-4-methoxyphenylNH₂ 0 407 3-carboxamido-5-methoxyphenyl NH₂ 0 408 4-carboxamidophenylNH₂ 0 409 3-fluoro-4-carboxamidephenyl NH₂ 0 4103-chloro-4-carboxamidephenyl NH₂ 0 411 3-hydroxy-4-carboxamidephenyl NH₂0 412 3-methoxy-4-carboxamidephenyl NH₂ 0 413 2-trifluoromethylphenylNH₂ 0 414 3-trifluoromethylphenyl NH₂ 0 415 4-trifluoromethylphenyl NH₂0 416 2-trifluoromethoxyphenyl NH₂ 0 417 3-trifluoromethoxyphenyl NH₂ 0418 4-trifluoromethoxyphenyl NH₂ 0 419 2-difluoromethoxyphenyl NH₂ 0 4203-difluoromethoxyphenyl NH₂ 0 421 4-difluoromethoxyphenyl NH₂ 0 4222-methylphenyl NH₂ 0 423 3-methylphenyl NH₂ 0 424 4-methylphenyl NH₂ 0425 2,4-dimethylphenyl NH₂ 0 426 3,4-dimethylphenyl NH₂ 0 4273,5-dimethylphenyl NH₂ 0 428 2-hydroxymethylphenyl NH₂ 0 4293-hydroxymethylphenyl NH₂ 0 430 3-(2-hydroxyprop-2-yl)phenyl NH₂ 0 4314-hydroxymethylphenyl NH₂ 0 432 2-carboxyphenyl NH₂ 0 4333-carboxyphenyl NH₂ 0 434 4-carboxyphenyl NH₂ 0 435 3-aminomethylphenylNH₂ 0 436 4-aminomethylphenyl NH₂ 0 4373-cyclopropanesulfonamidomethylphenyl NH₂ 0 4383-benzenesulfonamidomethyl NH₂ 0 439 3-(3,5-difluoro- NH₂ 0benzenesulfonamidomethyl)phenyl 4404-cyclopropanesulfonamidomethylphenyl NH₂ 0 4414-benzenesulfonamidomethylphenyl NH₂ 0 442 4-(3,5-difluoro- NH₂ 0benzenesulfonamidomethyl)phenyl 443 4-(1,2-dimethyl-1H-imidazole-5- NH₂0 sulfonamidomethyl)phenyl 444 3-dimethylsulfamoylphenyl NH₂ 0 4453-methylsulfamoylphenyl NH₂ 0 446 3-sulfamoylphenyl NH₂ 0 4473-methanesulfonamidophenyl NH₂ 0 448 4-dimethylsulfamoylphenyl NH₂ 0 4494-methylsulfamoylphenyl NH₂ 0 450 4-sulfamoylphenyl NH₂ 0 4514-methanesulfonamidophenyl NH₂ 0 4523-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl NH₂ 0 4533-[(2-carboxy-2,2-dimethylethyl)amino]phenyl NH₂ 0 4544-acetylamidophenyl NH₂ 0 455 3-acetylamidophenyl NH₂ 0 456 Phenyl2,5-dimethylpyrrol-1-yl 0 457 4-methylphenyl 2,5-dimethylpyrrol-1-yl 0458 Phenyl 4,5-dimethyl-1,2oxazol-4-yl 0 459 Phenyl 1H-pyrazol-4-yl 0460 Phenyl 1-methyl-1H-pyrazol-4-yl 0 461 Phenyl pyrimidin-5-yl 0 462Phenyl pyrimidin-2-yl 0 463 Phenyl pyrimidin-4-yl 0 464 Phenylpyridin-2-yl 0 465 Phenyl pyridin-3-yl 0 466 Phenyl pyridin-4-yl 0 467Phenyl 5-hydroxy-pyridin-3-yl 0 468 Phenyl 5-methoxy-pyridin-3-yl 0 469Phenyl 3-hydroxy-pyridin-4-yl 0 470 Phenyl 3-methoxy-pyridin-4-yl 0 471Phenyl 2-methoxy-pyridin-5-yl 0 472 Phenyl N,N-dimethylaminopyridin-5-yl0 473 Phenyl 4-methanesulfonylphenyl 0 474 Phenyl3-methanesulfonylphenyl 0 475 Phenyl N,N-dimethylaminomethylphenyl 0 476Phenyl 2-methoxyphenyl 0 477 Phenyl 3-methoxyphenyl 0 478 Phenyl4-methoxyphenyl 0 479 Phenyl 3,5-dimethoxyphenyl 0 480 Phenyl3,4-dimethoxyphenyl 0 481 Phenyl 3-hydroxy-4-methoxyphenyl 0 482 Phenyl3-hydroxy-5-methoxyphenyl 0 483 Phenyl quinolin-3-yl 0 484 Phenylcyclopropyl 0 485 Phenyl 3-hydroxymethylphenyl 0 486 Phenyl4-hydroxymethylphenyl 0 487 Phenyl 1-benzofuran-5-yl 0 488 Phenyl1-benzothiophen-5-yl 0 489 Phenyl 1H-indol-6-yl 0 490 Phenyl1H-indol-3-yl 0 491 Phenyl 1-methyl-1H-indol-5-yl 0 492 Phenyl1-methyl-1H-indol-6-yl 0 493 Phenyl 1H-indazol-5-yl 0 494 Phenyl1H-indazol-6-yl 0 495 Phenyl 1-methyl-1H-indazol-5-yl 0 496 Phenyl1-methyl-1H-indazol-6-yl 0 497 Phenyl 2-methyl-1,3-benzothiazol-5-yl 0498 Phenyl N,N-dimethylaminophen-4-yl 0 499 Phenyl4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl 0 500 Phenylbenzimidazol-5-yl 0 501 Phenyl 3-acetyl-1H-indol-6-yl 0 502 Phenylphenyl 0 503 Phenyl 4-hydroxphenyl 0 504 Phenyl 3-fluoro-5-hydroxyphenyl0 505 Phenyl 3-chloro-5-hydroxyphenyl 0 506 Phenyl 2-phenoxyphenyl 0 507Phenyl 3-phenoxyphenyl 0 508 Phenyl 4-phenoxyphenyl 0 509 Phenyl4-phenyl-1H-1,2,3-triazol-1-yl 0 510 Phenyl3-methoxyphenyl)-1H-1,2,3-triazol-1-yl 0 511 Phenyl4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl 0 512 Phenyl3-hydroxypropyl)-1H-1,2,3-triazol-1-yl 0 513 Phenyl benzylamino 0 514Phenyl benzyloxy 0 515 Phenyl piperazin-1-yl 0 516 Phenylpyrrolidin-1-yl 0 517 Phenyl 3-hydroxypyrrolidin-1-yl 0 518 Phenyl3-carboxypyrrolidin-1-yl 0 519 Phenyl 3-(dimethylamino)pyrrolidin-1-yl 0520 Phenyl 2-phenylpyrrolidin-1-yl 0 521 Phenyl1,2,3,6-tetrahydropyridin-4-yl 0 522 Phenyl3-(methoxycarbonyl)-1H-indol-6-yl] 0 523 Phenyl4-(cyclopropylcarbamoyl)phenyl 0 524 Phenyl2-[(2-hydroxyethyl)sulfamoyl]pheny 0 525 Phenyl naphthalen-2-yl 0 526Phenyl 4-methylphenyl 0 527 Phenyl 3-methanesulfonamidophenyl 0 5283-hydroxyphenyl 2,5-dimethylpyrrol-1-yl 0 529 3-hydroxyphenyl4,5-dimethyl-1,2oxazol-4-yl 0 530 3-hydroxyphenyl 1H-pyrazol-4-yl 0 5313-hydroxyphenyl 1-methyl-1H-pyrazol-4-yl 0 532 3-hydroxyphenylpyrimidin-5-yl 0 533 3-hydroxyphenyl pyrimidin-2-yl 0 5343-hydroxyphenyl pyrimidin-4-yl 0 535 3-hydroxyphenyl pyridin-2-yl 0 5363-hydroxyphenyl pyridin-3-yl 0 537 3-hydroxyphenyl pyridin-4-yl 0 5383-hydroxyphenyl 5-hydroxy-pyridin-3-yl 0 539 3-hydroxyphenyl5-methoxy-pyridin-3-yl 0 540 3-hydroxyphenyl 3-hydroxy-pyridin-4-yl 0541 3-hydroxyphenyl 3-methoxy-pyridin-4-yl 0 542 3-hydroxyphenylN,N-dimethylaminopyridin-5-yl 0 543 3-hydroxyphenyl4-methanesulfonylphenyl 0 544 3-hydroxyphenyl 3-methanesulfonylphenyl 0545 3-hydroxyphenyl N,N-dimethylaminomethylphenyl 0 546 3-hydroxyphenyl2-methoxyphenyl 0 547 3-hydroxyphenyl 3-methoxyphenyl 0 5483-hydroxyphenyl 4-methoxyphenyl 0 549 3-hydroxyphenyl3,5-dimethoxyphenyl 0 550 3-hydroxyphenyl 3,4-dimethoxyphenyl 0 5513-hydroxyphenyl 3-hydroxy-4-methoxyphenyl 0 552 3-hydroxyphenyl3-hydroxy-5-methoxyphenyl 0 553 3-hydroxyphenyl quinolin-3-yl 0 5543-hydroxyphenyl cyclopropyl 0 555 3-hydroxyphenyl 3-hydroxymethylphenyl0 556 3-hydroxyphenyl 4-hydroxymethylphenyl 0 557 3-hydroxyphenyl1-benzofuran-5-yl 0 558 3-hydroxyphenyl 1-benzothiophen-5-yl 0 5593-hydroxyphenyl 1H-indol-6-yl 0 560 3-hydroxyphenyl 1H-indol-3-yl 0 5613-hydroxyphenyl 1-methyl-1H-indol-5-yl 0 562 3-hydroxyphenyl1-methyl-1H-indol-6-yl 0 563 3-hydroxyphenyl 1H-indazol-5-yl 0 5643-hydroxyphenyl 1H-indazol-6-yl 0 565 3-hydroxyphenyl1-methyl-1H-indazol-5-yl 0 566 3-hydroxyphenyl 1-methyl-1H-indazol-6-yl0 567 3-hydroxyphenyl 2-methyl-1,3-benzothiazol-5-yl 0 5683-hydroxyphenyl N,N-dimethylaminophen-4-yl 0 569 3-hydroxyphenyl4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl 0 570 3-hydroxyphenylbenzimidazol-5-yl 0 571 3-hydroxyphenyl 3-acetyl-1H-indol-6-yl 0 5723-hydroxyphenyl phenyl 0 573 3-hydroxyphenyl 4-hydroxphenyl 0 5743-hydroxyphenyl 3-fluoro-5-hydroxyphenyl 0 575 3-hydroxyphenyl3-chloro-5-hydroxyphenyl 0 576 3-hydroxyphenyl 2-phenoxyphenyl 0 5773-hydroxyphenyl 3-phenoxyphenyl 0 578 3-hydroxyphenyl 4-phenoxyphenyl 0579 3-fluorophenyl 2,5-dimethylpyrrol-1-yl 0 580 3-fluorophenyl4,5-dimethyl-1,2oxazol-4-yl 0 581 3-fluorophenyl 1H-pyrazol-4-yl 0 5823-fluorophenyl 1-methyl-1H-pyrazol-4-yl 0 583 3-fluorophenylpyrimidin-5-yl 0 584 3-fluorophenyl pyrimidin-2-yl 0 585 3-fluorophenylpyrimidin-4-yl 0 586 3-fluorophenyl pyridin-2-yl 0 587 3-fluorophenylpyridin-3-yl 0 588 3-fluorophenyl pyridin-4-yl 0 589 3-fluorophenyl5-hydroxy-pyridin-3-yl 0 590 3-fluorophenyl 5-methoxy-pyridin-3-yl 0 5913-fluorophenyl 3-hydroxy-pyridin-4-yl 0 592 3-fluorophenyl3-methoxy-pyridin-4-yl 0 593 3-fluorophenylN,N-dimethylaminopyridin-5-yl 0 594 3-fluorophenyl4-methanesulfonylphenyl 0 595 3-fluorophenyl 3-methanesulfonylphenyl 0596 3-fluorophenyl N,N-dimethylaminomethylphenyl 0 597 3-fluorophenyl2-methoxyphenyl 0 598 3-fluorophenyl 3-methoxyphenyl 0 5993-fluorophenyl 4-methoxyphenyl 0 600 3-fluorophenyl 3,5-dimethoxyphenyl0 601 3-fluorophenyl 3,4-dimethoxyphenyl 0 602 3-fluorophenyl3-hydroxy-4-methoxyphenyl 0 603 3-fluorophenyl 3-hydroxy-5-methoxyphenyl0 604 3-fluorophenyl quinolin-3-yl 0 605 3-fluorophenyl cyclopropyl 0606 3-fluorophenyl 3-hydroxymethylphenyl 0 607 3-fluorophenyl4-hydroxymethylphenyl 0 608 3-fluorophenyl 1-benzofuran-5-yl 0 6093-fluorophenyl 1-benzothiophen-5-yl 0 610 3-fluorophenyl 1H-indol-6-yl 0611 3-fluorophenyl 1H-indol-3-yl 0 612 3-fluorophenyl1-methyl-1H-indol-5-yl 0 613 3-fluorophenyl 1-methyl-1H-indol-6-yl 0 6143-fluorophenyl 1H-indazol-5-yl 0 615 3-fluorophenyl 1H-indazol-6-yl 0616 3-fluorophenyl 1-methyl-1H-indazol-5-yl 0 617 3-fluorophenyl1-methyl-1H-indazol-6-yl 0 618 3-fluorophenyl2-methyl-1,3-benzothiazol-5-yl 0 619 3-fluorophenylN,N-dimethylaminophen-4-yl 0 620 3-fluorophenyl4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl 0 621 3-fluorophenylbenzimidazol-5-yl 0 622 3-fluorophenyl 3-acetyl-1H-indol-6-yl 0 6233-fluorophenyl phenyl 0 624 3-fluorophenyl 4-hydroxphenyl 0 6253-fluorophenyl 3-fluoro-5-hydroxyphenyl 0 626 3-fluorophenyl3-chloro-5-hydroxyphenyl 0 627 3-fluorophenyl 2-phenoxyphenyl 0 6283-fluorophenyl 3-phenoxyphenyl 0 629 3-fluorophenyl 4-phenoxyphenyl 0630 3-fluorophenyl 4-(cyclopropylcarbamoyl)phenyl 0 631 pyridin-2-ylN-pyrrolyl 0 632 pyridin-3-yl N-pyrrolyl 0 633 5-hydroxy-pyridin-3-ylN-pyrrolyl 0 634 5-methoxy-pyridin-3-yl N-pyrrolyl 0 635 pyridin-4-ylN-pyrrolyl 0 636 2-hydroxy-pyridin-4-yl N-pyrrolyl 0 6372-methoxy-pyridin-4-yl N-pyrrolyl 0 638 pyrimid-2-yl N-pyrrolyl 0 639pyrimid-4-yl N-pyrrolyl 0 640 pyrimid-5-yl N-pyrrolyl 0 641 indol-3-ylN-pyrrolyl 0 642 indol-4-yl N-pyrrolyl 0 643 indol-5-yl N-pyrrolyl 0 644indol-6-yl N-pyrrolyl 0 645 indol-7-yl N-pyrrolyl 0 646 indazol-3-ylN-pyrrolyl 0 647 indazol-4-yl N-pyrrolyl 0 648 indazol-5-yl N-pyrrolyl 0649 indazol-6-yl N-pyrrolyl 0 650 indazol-7-yl N-pyrrolyl 0 651benzimidazol-4-yl N-pyrrolyl 0 652 benzimidazol-5-yl N-pyrrolyl 0 6537-azaindol-3-yl N-pyrrolyl 0 654 7-azaindol-4-yl N-pyrrolyl 0 6557-azaindol-5-yl N-pyrrolyl 0 656 7-azaindol-6-yl N-pyrrolyl 0 657N-methyl-indolin-4-yl N-pyrrolyl 0 658 N-methyl-indolin-5-yl N-pyrrolyl0 659 N-methyl-indolin-6-yl N-pyrrolyl 0 660 N-methyl-indolin-7-ylN-pyrrolyl 0 661 1-benzothiophene-5-yl N-pyrrolyl 0 6621-benzothiophene-6-yl N-pyrrolyl 0 663 imidazo[1,2a]pyridin-6-ylN-pyrrolyl 0 664 imidazo[1,2a]pyridin-5-yl N-pyrrolyl 0 665imidazo[1,2a]pyridin-3-yl N-pyrrolyl 0 666 imidazo[1,2a]pyrazin-3-ylN-pyrrolyl 0 667 [1,2,4]triazolo[1,5a]pyridin-7-yl N-pyrrolyl 0 668benzyl N-pyrrolyl 0 669 phenethyl N-pyrrolyl 0 670 phenylmethanolN-pyrrolyl 0 671 2-hydroxy-prop-2-yl N-pyrrolyl 0 6723-hydroxy-prop-1-yl N-pyrrolyl 0 673 2-hydroxy-3-methyl-prop-2-ylN-pyrrolyl 0 674 2-amino-prop-2-yl N-pyrrolyl 0 675 2-methyl-prop-2-ylN-pyrrolyl 0 676 1-hydroxy-cyclohex-1-yl N-pyrrolyl 0 6771-amino-cyclohex-1-yl N-pyrrolyl 0 678 thiazol-4-yl N-pyrrolyl 0 679thiazol-5-yl N-pyrrolyl 0 680 1-methyl-imidazol-2-yl N-pyrrolyl 0 6811-methyl-imidazol-5-yl N-pyrrolyl 0 682 1,2-dimethyl-imidazol-4-ylN-pyrrolyl 0 683 1-methyl-pyrazol-4-yl N-pyrrolyl 0 6841-imidazol-methyl N-pyrrolyl 0 685 N-benzyl-N-methyl-aminomethylN-pyrrolyl 0 686 2,3-dihydro-1H-indol-6-yl N-pyrrolyl 0 687 cyclopropylN-pyrrolyl 0 688 dimethylaminomethyl N-pyrrolyl 0 689 pyridin-2-yl1H-indol-5-yl 0 690 pyridin-3-yl 1H-indol-5-yl 0 6915-hydroxy-pyridin-3-yl 1H-indol-5-yl 0 692 5-methoxy-pyridin-3-yl1H-indol-5-yl 0 693 pyridin-4-yl 1H-indol-5-yl 0 6942-hydroxy-pyridin-4-yl 1H-indol-5-yl 0 695 2-methoxy-pyridin-4-yl1H-indol-5-yl 0 696 pyrimid-2-yl 1H-indol-5-yl 0 697 pyrimid-4-yl1H-indol-5-yl 0 698 pyrimid-5-yl 1H-indol-5-yl 0 699 indol-3-yl1H-indol-5-yl 0 700 indol-4-yl 1H-indol-5-yl 0 701 indol-5-yl1H-indol-5-yl 0 702 indol-6-yl 1H-indol-5-yl 0 703 indol-7-yl1H-indol-5-yl 0 704 indazol-3-yl 1H-indol-5-yl 0 705 indazol-4-yl1H-indol-5-yl 0 706 indazol-5-yl 1H-indol-5-yl 0 707 indazol-6-yl1H-indol-5-yl 0 708 indazol-7-yl 1H-indol-5-yl 0 709 benzimidazol-4-yl1H-indol-5-yl 0 710 benzimidazol-5-yl 1H-indol-5-yl 0 7117-azaindol-3-yl 1H-indol-5-yl 0 712 7-azaindol-4-yl 1H-indol-5-yl 0 7137-azaindol-5-yl 1H-indol-5-yl 0 714 7-azaindol-6-yl 1H-indol-5-yl 0 715N-methyl-indolin-4-yl 1H-indol-5-yl 0 716 N-methyl-indolin-5-yl1H-indol-5-yl 0 717 N-methyl-indolin-6-yl 1H-indol-5-yl 0 718N-methyl-indolin-7-yl 1H-indol-5-yl 0 719 1-benzothiophene-5-yl1H-indol-5-yl 0 720 1-benzothiophene-6-yl 1H-indol-5-yl 0 721imidazo[1,2a]pyridin-6-yl 1H-indol-5-yl 0 722 imidazo[1,2a]pyridin-5-yl1H-indol-5-yl 0 723 imidazo[1,2a]pyridin-3-yl 1H-indol-5-yl 0 724imidazo[1,2a]pyrazin-3-yl 1H-indol-5-yl 0 725[1,2,4]triazolo[1,5a]pyridin-7-yl 1H-indol-5-yl 0 726 benzyl1H-indol-5-yl 0 727 phenethyl 1H-indol-5-yl 0 728 2-hydroxy-prop-2-yl1H-indol-5-yl 0 729 3-hydroxy-prop-1-yl 1H-indol-5-yl 0 7302-hydroxy-3-methyl-prop-2-yl 1H-indol-5-yl 0 731 2-amino-prop-2-yl1H-indol-5-yl 0 732 2-methyl-prop-2-yl 1H-indol-5-yl 0 7331-hydroxy-cyclohex-1-yl 1H-indol-5-yl 0 734 1-amino-cyclohex-1-yl1H-indol-5-yl 0 735 thiazol-4-yl 1H-indol-5-yl 0 736 thiazol-5-yl1H-indol-5-yl 0 737 1-methyl-imidazol-2-yl 1H-indol-5-yl 0 7381-methyl-imidazol-5-yl 1H-indol-5-yl 0 739 1,2-dimethyl-imidazol-4-yl1H-indol-5-yl 0 740 1-methyl-pyrazol-4-yl 1H-indol-5-yl 0 7411-imidazol-methyl 1H-indol-5-yl 0 742 N-benzyl-N-methyl-aminomethyl1H-indol-5-yl 0 743 2,3-dihydro-1H-indol-6-yl 1H-indol-5-yl 0 744cyclopropyl 1H-indol-5-yl 0 745 dimethylaminomethyl 1H-indol-5-yl 0 746pyridin-2-yl 3-hydroxphenyl 0 747 pyridin-3-yl 3-hydroxphenyl 0 7485-hydroxy-pyridin-3-yl 3-hydroxphenyl 0 749 5-methoxy-pyridin-3-yl3-hydroxphenyl 0 750 pyridin-4-yl 3-hydroxphenyl 0 7512-hydroxy-pyridin-4-yl 3-hydroxphenyl 0 752 2-methoxy-pyridin-4-yl3-hydroxphenyl 0 753 pyrimid-2-yl 3-hydroxphenyl 0 754 pyrimid-4-yl3-hydroxphenyl 0 755 pyrimid-5-yl 3-hydroxphenyl 0 756 indol-3-yl3-hydroxphenyl 0 757 indol-4-yl 3-hydroxphenyl 0 758 indol-5-yl3-hydroxphenyl 0 759 indol-6-yl 3-hydroxphenyl 0 760 indol-7-yl3-hydroxphenyl 0 761 indazol-3-yl 3-hydroxphenyl 0 762 indazol-4-yl3-hydroxphenyl 0 763 indazol-5-yl 3-hydroxphenyl 0 764 indazol-6-yl3-hydroxphenyl 0 765 indazol-7-yl 3-hydroxphenyl 0 766 benzimidazol-4-yl3-hydroxphenyl 0 767 benzimidazol-5-yl 3-hydroxphenyl 0 7687-azaindol-3-yl 3-hydroxphenyl 0 769 7-azaindol-4-yl 3-hydroxphenyl 0770 7-azaindol-5-yl 3-hydroxphenyl 0 771 7-azaindol-6-yl 3-hydroxphenyl0 772 N-methyl-indolin-4-yl 3-hydroxphenyl 0 773 N-methyl-indolin-5-yl3-hydroxphenyl 0 774 N-methyl-indolin-6-yl 3-hydroxphenyl 0 775N-methyl-indolin-7-yl 3-hydroxphenyl 0 776 1-benzothiophene-5-yl3-hydroxphenyl 0 777 1-benzothiophene-6-yl 3-hydroxphenyl 0 778imidazo[1,2a]pyridin-6-yl 3-hydroxphenyl 0 779 imidazo[1,2a]pyridin-5-yl3-hydroxphenyl 0 780 imidazo[1,2a]pyridin-3-yl 3-hydroxphenyl 0 781imidazo[1,2a]pyrazin-3-yl 3-hydroxphenyl 0 782 benzyl 3-hydroxphenyl 0783 phenethyl 3-hydroxphenyl 0 784 2-hydroxy-prop-2-yl 3-hydroxphenyl 0785 3-hydroxy-prop-1-yl 3-hydroxphenyl 0 7862-hydroxy-3-methyl-prop-2-yl 3-hydroxphenyl 0 787 2-amino-prop-2-yl3-hydroxphenyl 0 788 2-methyl-prop-2-yl 3-hydroxphenyl 0 7891-hydroxy-cyclohex-1-yl 3-hydroxphenyl 0 790 1-amino-cyclohex-1-yl3-hydroxphenyl 0 791 thiazol-4-yl 3-hydroxphenyl 0 792 thiazol-5-yl3-hydroxphenyl 0 793 1-methyl-imidazol-2-yl 3-hydroxphenyl 0 7941-methyl-imidazol-5-yl 3-hydroxphenyl 0 795 1,2-dimethyl-imidazol-4-yl3-hydroxphenyl 0 796 1-methyl-pyrazol-4-yl 3-hydroxphenyl 0 7971-imidazol-methyl 3-hydroxphenyl 0 798 N-benzyl-N-methyl-aminomethyl3-hydroxphenyl 0 799 2,3-dihydro-1H-indol-6-yl 3-hydroxphenyl 0 800cyclopropyl 3-hydroxphenyl 0 801 dimethylaminomethyl 3-hydroxphenyl 0802 pyridin-2-yl F 0 803 pyridin-3-yl F 0 804 5-hydroxy-pyridin-3-yl F 0805 5-methoxy-pyridin-3-yl F 0 806 pyridin-4-yl F 0 8072-hydroxy-pyridin-4-yl F 0 808 2-methoxy-pyridin-4-yl F 0 809pyrimid-2-yl F 0 810 pyrimid-4-yl F 0 811 pyrimid-5-yl F 0 812indol-3-yl F 0 813 indol-4-yl F 0 814 indol-5-yl F 0 815 indol-6-yl F 0816 indol-7-yl F 0 817 indazol-3-yl F 0 818 indazol-4-yl F 0 819indazol-5-yl F 0 820 indazol-6-yl F 0 821 indazol-7-yl F 0 822benzimidazol-4-yl F 0 823 benzimidazol-5-yl F 0 824 7-azaindol-3-yl F 0825 7-azaindol-4-yl F 0 826 7-azaindol-5-yl F 0 827 7-azaindol-6-yl F 0828 N-methyl-indolin-4-yl F 0 829 N-methyl-indolin-5-yl F 0 830N-methyl-indolin-6-yl F 0 831 N-methyl-indolin-7-yl F 0 8321-benzothiophene-5-yl F 0 833 1-benzothiophene-6-yl F 0 834imidazo[1,2a]pyridin-6-yl F 0 835 imidazo[1,2a]pyridin-5-yl F 0 836imidazo[1,2a]pyridin-3-yl F 0 837 imidazo[1,2a]pyrazin-3-yl F 0 838benzyl F 0 839 phenethyl F 0 840 2-hydroxy-prop-2-yl F 0 8413-hydroxy-prop-1-yl F 0 842 2-hydroxy-3-methyl-prop-2-yl F 0 8432-amino-prop-2-yl F 0 844 2-methyl-prop-2-yl F 0 8451-hydroxy-cyclohex-1-yl F 0 846 1-amino-cyclohex-1-yl F 0 847thiazol-4-yl F 0 848 thiazol-5-yl F 0 849 1-methyl-imidazol-2-yl F 0 8501-methyl-imidazol-5-yl F 0 851 1,2-dimethyl-imidazol-4-yl F 0 8521-methyl-pyrazol-4-yl F 0 853 1-imidazol-methyl F 0 854N-benzyl-N-methyl-aminomethyl F 0 855 2,3-dihydro-1H-indol-6-yl F 0 856cyclopropyl F 0 857 dimethylaminomethyl F 0 858 pyridin-2-yl NH₂ 0 859pyridin-3-yl NH₂ 0 860 5-hydroxy-pyridin-3-yl NH₂ 0 8615-methoxy-pyridin-3-yl NH₂ 0 862 pyridin-4-yl NH₂ 0 8632-hydroxy-pyridin-4-yl NH₂ 0 864 2-methoxy-pyridin-4-yl NH₂ 0 865pyrimid-2-yl NH₂ 0 866 pyrimid-4-yl NH₂ 0 867 pyrimid-5-yl NH₂ 0 868indol-3-yl NH₂ 0 869 indol-4-yl NH₂ 0 870 indol-5-yl NH₂ 0 871indol-6-yl NH₂ 0 872 indol-7-yl NH₂ 0 873 indazol-3-yl NH₂ 0 874indazol-4-yl NH₂ 0 875 indazol-5-yl NH₂ 0 876 indazol-6-yl NH₂ 0 877indazol-7-yl NH₂ 0 878 benzimidazol-4-yl NH₂ 0 879 benzimidazol-5-yl NH₂0 880 7-azaindol-3-yl NH₂ 0 881 7-azaindol-4-yl NH₂ 0 8827-azaindol-5-yl NH₂ 0 883 7-azaindol-6-yl NH₂ 0 884N-methyl-indolin-4-yl NH₂ 0 885 N-methyl-indolin-5-yl NH₂ 0 886N-methyl-indolin-6-yl NH₂ 0 887 N-methyl-indolin-7-yl NH₂ 0 8881-benzothiophene-5-yl NH₂ 0 889 1-benzothiophene-6-yl NH₂ 0 890imidazo[1,2a]pyridin-6-yl NH₂ 0 891 imidazo[1,2a]pyridin-5-yl NH₂ 0 892imidazo[1,2a]pyridin-3-yl NH₂ 0 893 imidazo[1,2a]pyrazin-3-yl NH₂ 0 894benzyl NH₂ 0 895 phenethyl NH₂ 0 896 2-hydroxy-prop-2-yl NH₂ 0 8973-hydroxy-prop-1-yl NH₂ 0 898 2-hydroxy-3-methyl-prop-2-yl NH₂ 0 8992-amino-prop-2-yl NH₂ 0 900 2-methyl-prop-2-yl NH₂ 0 9011-hydroxy-cyclohex-1-yl NH₂ 0 902 1-amino-cyclohex-1-yl NH₂ 0 903thiazol-4-yl NH₂ 0 904 thiazol-5-yl NH₂ 0 905 1-methyl-imidazol-2-yl NH₂0 906 1-methyl-imidazol-5-yl NH₂ 0 907 1,2-dimethyl-imidazol-4-yl NH₂ 0908 1-methyl-pyrazol-4-yl NH₂ 0 909 1-imidazol-methyl NH₂ 0 910N-benzyl-N-methyl-aminomethyl NH₂ 0 911 2,3-dihydro-1H-indol-6-yl NH₂ 0912 cyclopropyl NH₂ 0 913 dimethylaminomethyl NH₂ 0 914 4-pyridyl2,5-dimethylpyrrol-1-yl 0 915 4-pyridyl 4,5-dimethyl-1,2oxazol-4-yl 0916 4-pyridyl 1H-pyrazol-4-yl 0 917 4-pyridyl 1-methyl-1H-pyrazol-4-yl 0918 4-pyridyl pyrimidin-5-yl 0 919 4-pyridyl pyrimidin-2-yl 0 9204-pyridyl pyrimidin-4-yl 0 921 4-pyridyl pyridin-2-yl 0 922 4-pyridylpyridin-3-yl 0 923 4-pyridyl pyridin-4-yl 0 924 4-pyridyl5-hydroxy-pyridin-3-yl 0 925 4-pyridyl 5-methoxy-pyridin-3-yl 0 9264-pyridyl 3-hydroxy-pyridin-4-yl 0 927 4-pyridyl 3-methoxy-pyridin-4-yl0 928 4-pyridyl N,N-dimethylaminopyridin-5-yl 0 929 4-pyridyl4-methanesulfonylphenyl 0 930 4-pyridyl 3-methanesulfonylphenyl 0 9314-pyridyl N,N-dimethylaminomethylphenyl 0 932 4-pyridyl 2-methoxyphenyl0 933 4-pyridyl 3-methoxyphenyl 0 934 4-pyridyl 4-methoxyphenyl 0 9354-pyridyl 3,5-dimethoxyphenyl 0 936 4-pyridyl 3,4-dimethoxyphenyl 0 9374-pyridyl 3-hydroxy-4-methoxyphenyl 0 938 4-pyridyl3-hydroxy-5-methoxyphenyl 0 939 4-pyridyl quinolin-3-yl 0 940 4-pyridylcyclopropyl 0 941 4-pyridyl 3-hydroxymethylphenyl 0 942 4-pyridyl4-hydroxymethylphenyl 0 943 4-pyridyl 1-benzofuran-5-yl 0 944 4-pyridyl1-benzothiophen-5-yl 0 945 4-pyridyl 1H-indol-6-yl 0 946 4-pyridyl1H-indol-3-yl 0 947 4-pyridyl 1-methyl-1H-indol-5-yl 0 948 4-pyridyl1-methyl-1H-indol-6-yl 0 949 4-pyridyl 1H-indazol-5-yl 0 950 4-pyridyl1H-indazol-6-yl 0 951 4-pyridyl 1-methyl-1H-indazol-5-yl 0 952 4-pyridyl1-methyl-1H-indazol-6-yl 0 953 4-pyridyl 2-methyl-1,3-benzothiazol-5-yl0 954 4-pyridyl N,N-dimethylaminophen-4-yl 0 955 4-pyridyl4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl 0 956 4-pyridylbenzimidazol-5-yl 0 957 4-pyridyl 3-acetyl-1H-indol-6-yl 0 958 4-pyridylphenyl 0 959 4-pyridyl 4-hydroxphenyl 0 960 4-pyridyl3-fluoro-5-hydroxyphenyl 0 961 4-pyridyl 3-chloro-5-hydroxyphenyl 0 9624-pyridyl 2-phenoxyphenyl 0 963 4-pyridyl 3-phenoxyphenyl 0 9644-pyridyl 4-phenoxyphenyl 0 965 7-azaindol-3-yl 2,5-dimethylpyrrol-1-yl0 966 7-azaindol-3-yl 4,5-dimethyl-1,2oxazol-4-yl 0 967 7-azaindol-3-yl1H-pyrazol-4-yl 0 968 7-azaindol-3-yl 1-methyl-1H-pyrazol-4-yl 0 9697-azaindol-3-yl pyrimidin-5-yl 0 970 7-azaindol-3-yl pyrimidin-2-yl 0971 7-azaindol-3-yl pyrimidin-4-yl 0 972 7-azaindol-3-yl pyridin-2-yl 0973 7-azaindol-3-yl pyridin-3-yl 0 974 7-azaindol-3-yl pyridin-4-yl 0975 7-azaindol-3-yl 5-hydroxy-pyridin-3-yl 0 976 7-azaindol-3-yl5-methoxy-pyridin-3-yl 0 977 7-azaindol-3-yl 3-hydroxy-pyridin-4-yl 0978 7-azaindol-3-yl 3-methoxy-pyridin-4-yl 0 979 7-azaindol-3-ylN,N-dimethylaminopyridin-5-yl 0 980 7-azaindol-3-yl4-methanesulfonylphenyl 0 981 7-azaindol-3-yl 3-methanesulfonylphenyl 0982 7-azaindol-3-yl N,N-dimethylaminomethylphenyl 0 983 7-azaindol-3-yl2-methoxyphenyl 0 984 7-azaindol-3-yl 3-methoxyphenyl 0 9857-azaindol-3-yl 4-methoxyphenyl 0 986 7-azaindol-3-yl3,5-dimethoxyphenyl 0 987 7-azaindol-3-yl 3,4-dimethoxyphenyl 0 9887-azaindol-3-yl 3-hydroxy-4-methoxyphenyl 0 989 7-azaindol-3-yl3-hydroxy-5-methoxyphenyl 0 990 7-azaindol-3-yl quinolin-3-yl 0 9917-azaindol-3-yl cyclopropyl 0 992 7-azaindol-3-yl 3-hydroxymethylphenyl0 993 7-azaindol-3-yl 4-hydroxymethylphenyl 0 994 7-azaindol-3-yl1-benzofuran-5-yl 0 995 7-azaindol-3-yl 1-benzothiophen-5-yl 0 9967-azaindol-3-yl 1H-indol-6-yl 0 997 7-azaindol-3-yl 1H-indol-3-yl 0 9987-azaindol-3-yl 1-methyl-1H-indol-5-yl 0 999 7-azaindol-3-yl1-methyl-1H-indol-6-yl 0 1000 7-azaindol-3-yl 1H-indazol-5-yl 0 10017-azaindol-3-yl 1H-indazol-6-yl 0 1002 7-azaindol-3-yl1-methyl-1H-indazol-5-yl 0 1003 7-azaindol-3-yl 1-methyl-1H-indazol-6-yl0 1004 7-azaindol-3-yl 2-methyl-1,3-benzothiazol-5-yl 0 10057-azaindol-3-yl N,N-dimethylaminophen-4-yl 0 1006 7-azaindol-3-yl4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl 0 1007 7-azaindol-3-ylbenzimidazol-5-yl 0 1008 7-azaindol-3-yl 3-acetyl-1H-indol-6-yl 0 10097-azaindol-3-yl phenyl 0 1010 7-azaindol-3-yl 4-hydroxphenyl 0 10117-azaindol-3-yl 3-fluoro-5-hydroxyphenyl 0 1012 7-azaindol-3-yl3-chloro-5-hydroxyphenyl 0 1013 7-azaindol-3-yl 2-phenoxyphenyl 0 10147-azaindol-3-yl 3-phenoxyphenyl 0 1015 7-azaindol-3-yl 4-phenoxyphenyl 01016 thiazol-4-yl 2,5-dimethylpyrrol-1-yl 0 1017 thiazol-4-yl4,5-dimethyl-1,2oxazol-4-yl 0 1018 thiazol-4-yl 1H-pyrazol-4-yl 0 1019thiazol-4-yl 1-methyl-1H-pyrazol-4-yl 0 1020 thiazol-4-yl pyrimidin-5-yl0 1021 thiazol-4-yl pyrimidin-2-yl 0 1022 thiazol-4-yl pyrimidin-4-yl 01023 thiazol-4-yl pyridin-2-yl 0 1024 thiazol-4-yl pyridin-3-yl 0 1025thiazol-4-yl pyridin-4-yl 0 1026 thiazol-4-yl 5-hydroxy-pyridin-3-yl 01027 thiazol-4-yl 5-methoxy-pyridin-3-yl 0 1028 thiazol-4-yl3-hydroxy-pyridin-4-yl 0 1029 thiazol-4-yl 3-methoxy-pyridin-4-yl 0 1030thiazol-4-yl N,N-dimethylaminopyridin-5-yl 0 1031 thiazol-4-yl4-methanesulfonylphenyl 0 1032 thiazol-4-yl 3-methanesulfonylphenyl 01033 thiazol-4-yl N,N-dimethylaminomethylphenyl 0 1034 thiazol-4-yl2-methoxyphenyl 0 1035 thiazol-4-yl 3-methoxyphenyl 0 1036 thiazol-4-yl4-methoxyphenyl 0 1037 thiazol-4-yl 3,5-dimethoxyphenyl 0 1038thiazol-4-yl 3,4-dimethoxyphenyl 0 1039 thiazol-4-yl3-hydroxy-4-methoxyphenyl 0 1040 thiazol-4-yl 3-hydroxy-5-methoxyphenyl0 1041 thiazol-4-yl quinolin-3-yl 0 1042 thiazol-4-yl cyclopropyl 0 1043thiazol-4-yl 3-hydroxymethylphenyl 0 1044 thiazol-4-yl4-hydroxymethylphenyl 0 1045 thiazol-4-yl 1-benzofuran-5-yl 0 1046thiazol-4-yl 1-benzothiophen-5-yl 0 1047 thiazol-4-yl 1H-indol-6-yl 01048 thiazol-4-yl 1H-indol-3-yl 0 1049 thiazol-4-yl1-methyl-1H-indol-5-yl 0 1050 thiazol-4-yl 1-methyl-1H-indol-6-yl 0 1051thiazol-4-yl 1H-indazol-5-yl 0 1052 thiazol-4-yl 1H-indazol-6-yl 0 1053thiazol-4-yl 1-methyl-1H-indazol-5-yl 0 1054 thiazol-4-yl1-methyl-1H-indazol-6-yl 0 1055 thiazol-4-yl2-methyl-1,3-benzothiazol-5-yl 0 1056 thiazol-4-ylN,N-dimethylaminophen-4-yl 0 1057 thiazol-4-yl4-methyl-3,4-dihydro-2H-1,4- 0 benzoxazin-7-yl 1058 thiazol-4-ylbenzimidazol-5-yl 0 1059 thiazol-4-yl 3-acetyl-1H-indol-6-yl 0 1060thiazol-4-yl phenyl 0 1061 thiazol-4-yl 4-hydroxphenyl 0 1062thiazol-4-yl 3-fluoro-5-hydroxyphenyl 0 1063 thiazol-4-yl3-chloro-5-hydroxyphenyl 0 1064 thiazol-4-yl 2-phenoxyphenyl 0 1065thiazol-4-yl 3-phenoxyphenyl 0 1066 thiazol-4-yl 4-phenoxyphenyl 0 1067indol-6-yl 2,5-dimethylpyrrol-1-yl 0 1068 indol-6-yl4,5-dimethyl-1,2oxazol-4-yl 0 1069 indol-6-yl 1H-pyrazol-4-yl 0 1070indol-6-yl 1-methyl-1H-pyrazol-4-yl 0 1071 indol-6-yl pyrimidin-5-yl 01072 indol-6-yl pyrimidin-2-yl 0 1073 indol-6-yl pyrimidin-4-yl 0 1074indol-6-yl pyridin-2-yl 0 1075 indol-6-yl pyridin-3-yl 0 1076 indol-6-ylpyridin-4-yl 0 1077 indol-6-yl 5-hydroxy-pyridin-3-yl 0 1078 indol-6-yl5-methoxy-pyridin-3-yl 0 1079 indol-6-yl 3-hydroxy-pyridin-4-yl 0 1080indol-6-yl 3-methoxy-pyridin-4-yl 0 1081 indol-6-ylN,N-dimethylaminopyridin-5-yl 0 1082 indol-6-yl 4-methanesulfonylphenyl0 1083 indol-6-yl 3-methanesulfonylphenyl 0 1084 indol-6-ylN,N-dimethylaminomethylphenyl 0 1085 indol-6-yl 2-methoxyphenyl 0 1086indol-6-yl 3-methoxyphenyl 0 1087 indol-6-yl 4-methoxyphenyl 0 1088indol-6-yl 3,5-dimethoxyphenyl 0 1089 indol-6-yl 3,4-dimethoxyphenyl 01090 indol-6-yl 3-hydroxy-4-methoxyphenyl 0 1091 indol-6-yl3-hydroxy-5-methoxyphenyl 0 1092 indol-6-yl quinolin-3-yl 0 1093indol-6-yl cyclopropyl 0 1094 indol-6-yl 3-hydroxymethylphenyl 0 1095indol-6-yl 4-hydroxymethylphenyl 0 1096 indol-6-yl 1-benzofuran-5-yl 01097 indol-6-yl 1-benzothiophen-5-yl 0 1098 indol-6-yl 1H-indol-6-yl 01099 indol-6-yl 1H-indol-3-yl 0 1100 indol-6-yl 1-methyl-1H-indol-5-yl 01101 indol-6-yl 1-methyl-1H-indol-6-yl 0 1102 indol-6-yl 1H-indazol-5-yl0 1103 indol-6-yl 1H-indazol-6-yl 0 1104 indol-6-yl1-methyl-1H-indazol-5-yl 0 1105 indol-6-yl 1-methyl-1H-indazol-6-yl 01106 indol-6-yl 2-methyl-1,3-benzothiazol-5-yl 0 1107 indol-6-ylN,N-dimethylaminophen-4-yl 0 1108 indol-6-yl4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl 0 1109 indol-6-ylbenzimidazol-5-yl 0 1110 indol-6-yl 3-acetyl-1H-indol-6-yl 0 1111indol-6-yl phenyl 0 1112 indol-6-yl 4-hydroxphenyl 0 1113 indol-6-yl3-fluoro-5-hydroxyphenyl 0 1114 indol-6-yl 3-chloro-5-hydroxyphenyl 01115 indol-6-yl 2-phenoxyphenyl 0 1116 indol-6-yl 3-phenoxyphenyl 0 1117indol-6-yl 4-phenoxyphenyl 0 1118 pyrrolidin-1-yl-methyl phenyl 0 11194-phenylpiperazin-1-yl-methyl phenyl 0 11203-(1H-imidazol-1-yl)propylaminomethyl phenyl 0 1121 benzylaminomethylphenyl 0 1122 hydroxymethyl phenyl 0 1123 imidazo[1,2-a]pyrazin-3-ylquinolin-3-yl 0 1124 3-hydroxy-prop-1-yl quinolin-3-yl 0 11254-carboxy-1H-indol-6-yl Hydrogen 0 1126 4-carboxamide-1H-indol-6-ylHydrogen 0 1127 3-benzamidyl Hydrogen 0 11281-benzenesulfonyl-1H-indol-3-yl Hydrogen 0 1129 1H-indol-3-yl Hydrogen 01130 3-carbomethoxy-phenyl Hydrogen 0 1131 3-carbamoyl-5-methoxy-phenylHydrogen 0 1132 4-pyridyl 1H-pyrazol-3-yl 0 1133 Phenyl1,3,5-trimethyl-1H-pyrazol-4-yl 0 1134 1-hydroxy-1-methyl-ethyl2,5-dimethyl-pyrrol-1-yl 0 1135 3-carbamoyl-phenyl2,5-dimethyl-pyrrol-1-yl 0 1136 3-carboxy-phenyl2,5-dimethyl-pyrrol-1-yl 0 1137 3-hydroxymethyl-phenyl2,5-dimethyl-pyrrol-1-yl 0 1138 Phenyl-hydroxymethyl2,5-dimethyl-pyrrol-1-yl 0 1139 3-acetylamino-phenyl2,5-dimethyl-pyrrol-1-yl 0 1140 Cyclopropyl 2,5-dimethyl-pyrrol-1-yl 01141 3-methoxy-phenyl 2,5-dimethyl-pyrrol-1-yl 0 1142 PhenylBenzo[1,3]dioxol-5-yl-3-phenyl 0 1143 Phenyl Isoquinolin-6-yl 0 1144Phenyl Benzofuran-2-yl 0 1145 Phenyl Quinolin-8-yl 0 1146 Phenyl2-amino-pyrimidin-5-yl 0 1147 4-amino-phenyl 1H-indol-6-yl 0 11484-carboxy-phenyl 1H-indol-6-yl 0 1149 4-methoxy-phenyl 1H-indol-6-yl 01150 4-carbamoyl-phenyl 1H-indol-6-yl 0 11514-(piperazine-1-carbonyl)-phenyl 1H-indol-6-yl 0 11524-acetylamino-phenyl 1H-indol-6-yl 0 11534-[(pyridine-3-carbonyl)-amino]-phenyl 1H-indol-6-yl 0 11544-methanesulfonylamino-phenyl 1H-indol-6-yl 0 11554-(thiophene-2-sulfonylamino)-phenyl 1H-indol-6-yl 0 1156 thiazol-4-yl3-(Methoxycarbonyl)-1H-indol-6-yl 0 1157 3-hydroxyphenyl3-chloro-1H-indol-6-yl 0 1158 3-hydroxyphenyl3-(2-acetamidoethyl)-1H-indol-6-yl 0 11593-(N,N-dimethylsulfamoyl)phenyl Fluoro 0 11604-(tetrahydro-2H-pyran-4-yloxy)phenyl 1H-indol-6-yl 0 11614-morpholinophenyl 1H-indol-6-yl 0 1162 3-carbamoylphenyl 1H-indol-6-yl0 1163 4-Fluorophenyl 1H-indol-6-yl 0 1164 2,4-Difluorophenyl1H-indol-6-yl 0 1165 3-Acetamidophenyl 1H-indol-6-yl 0 11663-(nicotinamido)phenyl 1H-indol-6-yl 0 1167 3-(3-chloro-4- 1H-indol-6-yl0 fluorophenylsulfonamido)phenyl 1168 3-aminophenyl 1H-indol-6-yl 0 11693-(methylsulfonamido)phenyl 1H-indol-6-yl 0 11703-(thiophene-2-sulfonamido)phenyl 1H-indol-6-yl 0 11713-acetamido-5-fluorophenyl 1H-indol-6-yl 0 1172 Phenyl indolin-6-yl 01173 3-hydroxyphenyl indolin-6-yl 0 1174 6-aminopyridin-2-yl1H-indol-6-yl 0 1175 2-aminopyridin-4-yl 1H-indol-6-yl 0 11763-hydroxyphenyl benzo[d][1,3]dioxol-5-yl 0 1177 3-hydroxyphenyl4-amino-3-methoxyphenyl 0 1178 2-hydroxyethyl 1H-indol-6-yl 0 11791-amino-1-methyl-ethyl 1H-indol-6-yl 0 1180

1H-indol-6-yl 0 1181 1-hydroxy-1-methyl-ethyl 1H-indol-6-yl 0 11823-(hydroxymethyl)phenyl 1H-indol-6-yl 0 1183 Phenyl2-carboxy-1H-indol-6-yl 0 1184 Phenyl 2-(ethylcarboxy)-1H-indol-6-yl 01185 3-carbamoyl-5-methoxyphenyl 1H-indol-6-yl 0 1186 3-hydroxyphenyl2-carboxy-1H-indol-6-yl 0 1187 4-methoxyphenyl 2-carboxy-1H-indol-6-yl 01188 4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl 1H-indol-6-yl 0 1189Phenyl 3-acetamidophenyl 0 1190 5-amino-1H-1,3-benzodiazol-1-ylmethylPhenyl 0 1191 pyridin-4-yl 4-methylphenyl 0 1192 3-hydroxyphenyl4-methylphenyl 0 1193

Phenyl 0 1194 3-hydroxyphenyl 3-methanesulfonamidophenyl 0 11953-hydroxyphenyl 3-carbamoylphenyl 0 1196 3-hydroxyphenyl1-(benzenesulfonyl)-1H-indol-3-yl 0 1197

3-hydroxyphenyl 0 1198 3-carbamoylphenyl NH₂ 0 1190 3-carboxyphenyl NH₂0 1191 3-(morpholine-4-carbonyl)-phenyl H 0 11923-methylcarbamoyl-phenyl H 0 1193 3-dimethylcarbamoyl-phenyl H 0 11943-(4-methyl-piperazine-1-carbonyl)-phenyl H 0 11953-(4-phenyl-piperazine-1-carbonyl)- H 0 phenyl 1196 4-pyridyl indol-1-yl0 1197 4-pyridyl imidazol-1-yl 0 1198 4-pyridyl [1,2,4]triazol-1-yl 01199 Phenyl Imidazol-1-yl 0 1200 Phenyl Pyrazol-1-yl 0 1201 Phenyl[1,2,4]triazol-1-yl 0 1202 Phenyl Benzoimidazol-1-yl 0 1203 PhenylIndazol-1-yl 0 1204 Phenyl Indol-1-yl 0 1205 4-pyridylbenzoimidazol-1-yl 0

Exemplary embodiments include compounds having the formula (XIX) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹, R², R³ and m are defined hereinbelow in Table 2.

TABLE 2 Entry R¹ R² R³ m 1 Phenyl N-pyrrolyl 1H-tetrazol-5-yl 0 23-hydroxyphenyl N-pyrrolyl 1H-tetrazol-5-yl 0 3 3-fluorophenylN-pyrrolyl 1H-tetrazol-5-yl 0 4 indol-6-yl N-pyrrolyl 1H-tetrazol-5-yl 05 pyridin-4-yl N-pyrrolyl 1H-tetrazol-5-yl 0 6 7-azaindol-3-ylN-pyrrolyl 1H-tetrazol-5-yl 0 7 thiazol-4-yl N-pyrrolyl 1H-tetrazol-5-yl0 8 Phenyl indol-6-yl 1H-tetrazol-5-yl 0 9 3-hydroxyphenyl indol-6-yl1H-tetrazol-5-yl 0 10 3-fluorophenyl indol-6-yl 1H-tetrazol-5-yl 0 11indol-6-yl indol-6-yl 1H-tetrazol-5-yl 0 12 pyridin-4-yl indol-6-yl1H-tetrazol-5-yl 0 13 7-azaindol-3-yl indol-6-yl 1H-tetrazol-5-yl 0 14thiazol-4-yl indol-6-yl 1H-tetrazol-5-yl 0 15 Phenyl 3-hydroxyphenyl1H-tetrazol-5-yl 0 16 3-hydroxyphenyl 3-hydroxyphenyl 1H-tetrazol-5-yl 017 3-fluorophenyl 3-hydroxyphenyl 1H-tetrazol-5-yl 0 18 indol-6-yl3-hydroxyphenyl 1H-tetrazol-5-yl 0 19 pyridin-4-yl 3-hydroxyphenyl1H-tetrazol-5-yl 0 20 7-azaindol-3-yl 3-hydroxyphenyl 1H-tetrazol-5-yl 021 thiazol-4-yl 3-hydroxyphenyl 1H-tetrazol-5-yl 0 22 Phenyl N-pyrrolylmethanesulfonamidocarbonyl 0 23 3-hydroxyphenyl N-pyrrolylmethanesulfonamidocarbonyl 0 24 3-fluorophenyl N-pyrrolylmethanesulfonamidocarbonyl 0 25 indol-6-yl N-pyrrolylmethanesulfonamidocarbonyl 0 26 pyridin-4-yl N-pyrrolylmethanesulfonamidocarbonyl 0 27 7-azaindol-3-yl N-pyrrolylmethanesulfonamidocarbonyl 0 28 thiazol-4-yl N-pyrrolylmethanesulfonamidocarbonyl 0 29 Phenyl indol-6-ylmethanesulfonamidocarbonyl 0 30 3-hydroxyphenyl indol-6-ylmethanesulfonamidocarbonyl 0 31 3-fluorophenyl indol-6-ylmethanesulfonamidocarbonyl 0 32 indol-6-yl indol-6-ylmethanesulfonamidocarbonyl 0 33 pyridin-4-yl indol-6-ylmethanesulfonamidocarbonyl 0 34 7-azaindol-3-yl indol-6-ylmethanesulfonamidocarbonyl 0 35 thiazol-4-yl indol-6-ylmethanesulfonamidocarbonyl 0 36 Phenyl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 37 3-hydroxyphenyl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 38 3-fluorophenyl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 39 indol-6-yl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 40 pyridin-4-yl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 41 7-azaindol-3-yl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 42 thiazol-4-yl 3-hydroxyphenylmethanesulfonamidocarbonyl 0 43 Phenyl N-pyrrolylaminosulfonamidocarbonyl 0 44 3-hydroxyphenyl N-pyrrolylaminosulfonamidocarbonyl 0 45 3-fluorophenyl N-pyrrolylaminosulfonamidocarbonyl 0 46 indol-6-yl N-pyrrolylaminosulfonamidocarbonyl 0 47 pyridin-4-yl N-pyrrolylaminosulfonamidocarbonyl 0 48 7-azaindol-3-yl N-pyrrolylaminosulfonamidocarbonyl 0 49 thiazol-4-yl N-pyrrolylaminosulfonamidocarbonyl 0 50 Phenyl indol-6-yl aminosulfonamidocarbonyl0 51 3-hydroxyphenyl indol-6-yl aminosulfonamidocarbonyl 0 523-fluorophenyl indol-6-yl aminosulfonamidocarbonyl 0 53 indol-6-ylindol-6-yl aminosulfonamidocarbonyl 0 54 pyridin-4-yl indol-6-ylaminosulfonamidocarbonyl 0 55 7-azaindol-3-yl indol-6-ylaminosulfonamidocarbonyl 0 56 thiazol-4-yl indol-6-ylaminosulfonamidocarbonyl 0 57 Phenyl 3-hydroxyphenylaminosulfonamidocarbonyl 0 58 3-hydroxyphenyl 3-hydroxyphenylaminosulfonamidocarbonyl 0 59 3-fluorophenyl 3-hydroxyphenylaminosulfonamidocarbonyl 0 60 indol-6-yl 3-hydroxyphenylaminosulfonamidocarbonyl 0 61 pyridin-4-yl 3-hydroxyphenylaminosulfonamidocarbonyl 0 62 7-azaindol-3-yl 3-hydroxyphenylaminosulfonamidocarbonyl 0 63 thiazol-4-yl 3-hydroxyphenylaminosulfonamidocarbonyl 0 64 Phenyl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 65 3-hydroxyphenyl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 66 3-fluorophenyl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 67 indol-6-yl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 68 pyridin-4-yl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 69 7-azaindol-3-yl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 70 thiazol-4-yl N-pyrrolyl morpholin-4-yl- 0sulfonamidocarbonyl 71 Phenyl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 72 3-hydroxyphenyl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 73 3-fluorophenyl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 74 indol-6-yl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 75 pyridin-4-yl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 76 7-azaindol-3-yl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 77 thiazol-4-yl indol-6-yl morpholin-4-yl- 0sulfonamidocarbonyl 78 Phenyl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 79 3-hydroxyphenyl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 80 3-fluorophenyl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 81 indol-6-yl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 82 pyridin-4-yl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 83 7-azaindol-3-yl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 84 thiazol-4-yl 3-hydroxyphenyl morpholin-4-yl- 0sulfonamidocarbonyl 85 Phenyl N-pyrrolyl 1,1-dioxo-4-thiomorpholin-4-yl-0 sulfonamidocarbonyl 86 3-hydroxyphenyl N-pyrrolyl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 87 3-fluorophenylN-pyrrolyl 1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 88indol-6-yl N-pyrrolyl 1,1-dioxo-4-thiomorpholin-4-yl- 0sulfonamidocarbonyl 89 pyridin-4-yl N-pyrrolyl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 90 7-azaindol-3-ylN-pyrrolyl 1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 91thiazol-4-yl N-pyrrolyl 1,1-dioxo-4-thiomorpholin-4-yl- 0sulfonamidocarbonyl 92 Phenyl indol-6-yl 1,1-dioxo-4-thiomorpholin-4-yl-0 sulfonamidocarbonyl 93 3-hydroxyphenyl indol-6-yl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 94 3-fluorophenylindol-6-yl 1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 95indol-6-yl indol-6-yl 1,1-dioxo-4-thiomorpholin-4-yl- 0sulfonamidocarbonyl 96 pyridin-4-yl indol-6-yl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 97 7-azaindol-3-ylindol-6-yl 1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 98thiazol-4-yl indol-6-yl 1,1-dioxo-4-thiomorpholin-4-yl- 0sulfonamidocarbonyl 99 Phenyl 3-hydroxyphenyl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 1003-hydroxyphenyl 3-hydroxyphenyl 1,1-dioxo-4-thiomorpholin-4-yl- 0sulfonamidocarbonyl 101 3-fluorophenyl 3-hydroxyphenyl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 102 indol-6-yl3-hydroxyphenyl 1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl103 pyridin-4-yl 3-hydroxyphenyl 1,1-dioxo-4-thiomorpholin-4-yl- 0sulfonamidocarbonyl 104 7-azaindol-3-yl 3-hydroxyphenyl1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl 105 thiazol-4-yl3-hydroxyphenyl 1,1-dioxo-4-thiomorpholin-4-yl- 0 sulfonamidocarbonyl106 Phenyl N-pyrrolyl sulfonamide 0 107 3-hydroxyphenyl N-pyrrolylsulfonamide 0 108 3-fluorophenyl N-pyrrolyl sulfonamide 0 109 indol-6-ylN-pyrrolyl sulfonamide 0 110 pyridin-4-yl N-pyrrolyl sulfonamide 0 1117-azaindol-3-yl N-pyrrolyl sulfonamide 0 112 thiazol-4-yl N-pyrrolylsulfonamide 0 113 Phenyl indol-6-yl sulfonamide 0 114 3-hydroxyphenylindol-6-yl sulfonamide 0 115 3-fluorophenyl indol-6-yl sulfonamide 0 116indol-6-yl indol-6-yl sulfonamide 0 117 pyridin-4-yl indol-6-ylsulfonamide 0 118 7-azaindol-3-yl indol-6-yl sulfonamide 0 119thiazol-4-yl indol-6-yl sulfonamide 0 120 Phenyl 3-hydroxyphenylsulfonamide 0 121 3-hydroxyphenyl 3-hydroxyphenyl sulfonamide 0 1223-fluorophenyl 3-hydroxyphenyl sulfonamide 0 123 indol-6-yl3-hydroxyphenyl sulfonamide 0 124 pyridin-4-yl 3-hydroxyphenylsulfonamide 0 125 7-azaindol-3-yl 3-hydroxyphenyl sulfonamide 0 126thiazol-4-yl 3-hydroxyphenyl sulfonamide 0 127 Phenyl N-pyrrolylN-acetyl-sulfonamido 0 128 3-hydroxyphenyl N-pyrrolylN-acetyl-sulfonamido 0 129 3-fluorophenyl N-pyrrolylN-acetyl-sulfonamido 0 130 indol-6-yl N-pyrrolyl N-acetyl-sulfonamido 0131 pyridin-4-yl N-pyrrolyl N-acetyl-sulfonamido 0 132 7-azaindol-3-ylN-pyrrolyl N-acetyl-sulfonamido 0 133 thiazol-4-yl N-pyrrolylN-acetyl-sulfonamido 0 134 Phenyl indol-6-yl N-acetyl-sulfonamido 0 1353-hydroxyphenyl indol-6-yl N-acetyl-sulfonamido 0 136 3-fluorophenylindol-6-yl N-acetyl-sulfonamido 0 137 indol-6-yl indol-6-ylN-acetyl-sulfonamido 0 138 pyridin-4-yl indol-6-yl N-acetyl-sulfonamido0 139 7-azaindol-3-yl indol-6-yl N-acetyl-sulfonamido 0 140 thiazol-4-ylindol-6-yl N-acetyl-sulfonamido 0 141 Phenyl 3-hydroxyphenylN-acetyl-sulfonamido 0 142 3-hydroxyphenyl 3-hydroxyphenylN-acetyl-sulfonamido 0 143 3-fluorophenyl 3-hydroxyphenylN-acetyl-sulfonamido 0 144 indol-6-yl 3-hydroxyphenylN-acetyl-sulfonamido 0 145 pyridin-4-yl 3-hydroxyphenylN-acetyl-sulfonamido 0 146 7-azaindol-3-yl 3-hydroxyphenylN-acetyl-sulfonamido 0 147 thiazol-4-yl 3-hydroxyphenylN-acetyl-sulfonamido 0 148 5-1H-indolyl H 1H-tetrazol-5-yl 0 1493-1H-pyrrolo[2,3- H 1H-tetrazol-5-yl 0 b]pyridine 150 6-1H-indolyl H1H-tetrazol-5-yl 0 151

H 1H-tetrazol-5-yl 0 152 3-1H-indolyl H 1H-tetrazol-5-yl 0 1532-hydroxymethylphenyl H 1H-tetrazol-5-yl 0

Exemplary embodiments include compounds having the formula (XX) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹ and R² are defined herein below inTable 3.

TABLE 3 Entry R¹ R²  1 phenyl N-pyrrolyl  2 4-fluorophenyl N-pyrrolyl  3methoxymethyl N-pyrrolyl  4 indol-6-yl N-pyrrolyl  5 phenyl indol-6-yl 6 4-fluorophenyl indol-6-yl  7 methoxymethyl indol-6-yl  8 indol-6-ylindol-6-yl  9 phenyl 3-hydroxyphenyl 10 4-fluorophenyl 3-hydroxyphenyl11 methoxymethyl 3-hydroxyphenyl 12 indol-6-yl 3-hydroxyphenyl 13 phenylN-pyrrolidinyl 14 4-fluorophenyl N-pyrrolidinyl 15 methoxymethylN-pyrrolidinyl 16 indol-6-yl N-pyrrolidinyl

Exemplary embodiments include compounds having the formula (XXI) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹ and R² are defined herein below inTable 4.

TABLE 4 Entry R¹ R²  1 phenyl N-pyrrolyl  2 4-fluorophenyl N-pyrrolyl  3methoxymethyl N-pyrrolyl  4 indol-6-yl N-pyrrolyl  5 phenyl indol-6-yl 6 4-fluorophenyl indol-6-yl  7 methoxymethyl indol-6-yl  8 indol-6-ylindol-6-yl  9 phenyl 3-hydroxyphenyl 10 4-fluorophenyl 3-hydroxyphenyl11 methoxymethyl 3-hydroxyphenyl 12 indol-6-yl 3-hydroxyphenyl 13 phenylN-pyrrolidinyl 14 4-fluorophenyl N-pyrrolidinyl 15 methoxymethylN-pyrrolidinyl 16 indol-6-yl N-pyrrolidinyl

Exemplary embodiments include compounds having the formula (XXII) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹, R², X¹, X², and X³ are definedherein below in Table 5.

TABLE 5 Entry R¹ R² X¹ X² X³  1 phenyl N-pyrrolyl CH N CH  24-fluorophenyl N-pyrrolyl CH N CH  3 3-methoxyphenyl N-pyrrolyl CH N CH 4 indol-6-yl N-pyrrolyl CH N CH  5 2-hydroxy-prop-2-yl N-pyrrolyl CH NCH  6 phenyl indol-6-yl CH N CH  7 4-fluorophenyl indol-6-yl CH N CH  83-methoxyphenyl indol-6-yl CH N CH  9 indol-6-yl indol-6-yl CH N CH 102-hydroxy-prop-2-yl indol-6-yl CH N CH 11 phenyl N-pyrrolyl CF CH CH 124-fluorophenyl N-pyrrolyl CF CH CH 13 3-methoxyphenyl N-pyrrolyl CF CHCH 14 indol-6-yl N-pyrrolyl CF CH CH 15 2-hydroxy-prop-2-yl N-pyrrolylCF CH CH 16 phenyl indol-6-yl CF CH CH 17 4-fluorophenyl indol-6-yl CFCH CH 18 3-methoxyphenyl indol-6-yl CF CH CH 19 indol-6-yl indol-6-yl CFCH CH 20 2-hydroxy-prop-2-yl indol-6-yl CF CH CH 21 phenyl N-pyrrolyl CHCF CH 22 4-fluorophenyl N-pyrrolyl CH CF CH 23 3-methoxyphenylN-pyrrolyl CH CF CH 24 indol-6-yl N-pyrrolyl CH CF CH 252-hydroxy-prop-2-yl N-pyrrolyl CH CF CH 26 phenyl indol-6-yl CH CF CH 274-fluorophenyl indol-6-yl CH CF CH 28 3-methoxyphenyl indol-6-yl CH CFCH 29 indol-6-yl indol-6-yl CH CF CH 30 2-hydroxy-prop-2-yl indol-6-ylCH CF CH 31 phenyl N-pyrrolyl CH CCl CH 32 4-fluorophenyl N-pyrrolyl CHCCl CH 33 3-methoxyphenyl N-pyrrolyl CH CCl CH 34 indol-6-yl N-pyrrolylCH CCl CH 35 2-hydroxy-prop-2-yl N-pyrrolyl CH CCl CH 36 phenylindo1-6-y1 CH CCl CH 37 4-fluorophenyl indol-6-yl CH CCl CH 383-methoxyphenyl indol-6-yl CH CCl CH 39 indol-6-yl indol-6-yl CH CCl CH40 2-hydroxy-prop-2-yl indol-6-yl CH CCl CH

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name3-(3-Methylsulfamoyl-phenylethynyl)-2-pyrrol-1-yl-benzoic acid.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name 3-[2-(1H-indol-5-yl)ethynyl]benzoic acid.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name 2-amino-3-[2-(1H-indol-6-yl)ethynyl]benzoic acid.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name3-[(E)-2-(4-fluorophenyl)ethenyl]-2-(1H-pyrrol-1-yl)benzoic acid.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name3-[2-(4-fluorophenyl)ethyl]-2-(1H-pyrrol-1-yl)benzoic acid.

For the purposes of the present invention, a compound depicted by theracemic formula will stand equally well for either of the twoenantiomers having the formula or mixtures thereof, or in the case wherea second chiral center is present, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

PROCESS

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art. Standard synthetic methods andprocedures for the preparation of organic molecules and functional grouptransformations and manipulations can be readily obtained from therelevant scientific literature or from standard textbooks in the field.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions can vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures. Those skilled in the art of organic synthesiswill recognize that the nature and order of the synthetic stepspresented can be varied for the purpose of optimizing the formation ofthe compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & Sons, 1991), and subsequent editions, theentire disclosure of which is incorporated by reference herein for allpurposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The compounds of these teachings can be prepared by methods known in theart of organic chemistry. The reagents used in the preparation of thecompounds of these teachings can be either commercially obtained or canbe prepared by standard procedures described in the literature. Forexample, compounds of the present invention can be prepared according tothe method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. In accordance with thisinvention, compounds in the genus may be produced by one of thefollowing reaction schemes.

Compounds of formula (I) may be prepared according to the processoutlined in schemes 1-21.

Accordingly, a suitably substituted compound of the formula (1), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of the formula (2), a known compound orcompound prepared by known methods, in the presence of an acid such ashydrochloric acid, sulfuric acid, trifluoroacetic acid, and the like, inan organic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, methylene chloride and the like,optionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (3). Alternatively, a compound of theformula (1) may be reacted with trimethylsilyldiazomethane in an organicsolvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran,1,4-dioxane, N, N-dimethylformamide, and the like to provide a compoundof the formula (3). A compound of the formula (3) is then reacted with acompound of the formula (4), a known compound or compound prepared byknown methods, in the presence of a catalyst, such as 4-chloropyridinehydrochloride, in an organic solvent such as methylene chloride,1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like optionally heated, optionally heatedwith microwave irradiation to provide a compound of the formula (5).Alternatively, a compound of the formula (3) reacted with a compound ofthe formula (6), a known compound or compound prepared by known methods,in the presence of an acid such as hydrochloric acid, sulfuric acid,trifluoroacetic acid, acetic acid, and the like, in an organic solventsuch as methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like,optionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (5).

A compound of the formula (5) is reacted with a compound of the formula(7), a known compound or compound prepared by known methods, in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (8). Alternatively, a compound of the formula (5) is reactedwith trimethylsilyl acetylene in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (9). A compound of the formula (9) is then deprotected byremoval of the trimethylsily moiety by reacting a compound of theformula (9) with a fluoride source such as tetrabutylammonium fluoride,and the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like to provide acompound of the formula (10). A compound of the formula (10) is reactedwith a compound of the formula (11), a known compound or compoundprepared by known methods wherein X is a chloride, bromide, iodide,methanesulfonate, trifluoromethanesulfonate, tosylate, and the like inthe presence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (8). A compound of the formula (8) is reacted with a basesuch as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodiumcarbonate, lithium carbonate, potassium carbonate, and the like, in anorganic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(12).

A compound of the formula (13) is reacted with a compound of the formula(7), a known compound or compound prepared by known methods, in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (14). Alternatively, a compound of the formula (13) isreacted with trimethylsilyl acetylene in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (15). A compound of the formula (15) is then deprotected byremoval of the trimethylsily moiety by reacting a compound of theformula (15) with a fluoride source such as tetrabutylammonium fluoride,the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like to provide acompound of the formula (16). A compound of the formula (16) is reactedwith a compound of the formula (11), a known compound or compoundprepared by known methods wherein X is a chloride, bromide, iodide,methanesulfonate, trifluoromethanesulfonate, tosylate, and the like inthe presence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (14). A compound of the formula (14) is reacted with a basesuch as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodiumcarbonate, lithium carbonate, potassium carbonate, and the like, in anorganic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(17).

A compound of the formula (18) a known compound or compound prepared byknown methods, is reacted with sodium nitrite in the presence of an acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, and the like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the likeoptionally heated, optionally heated with microwave irradiation. Furtherreaction with a compound of the formula (19) wherein M is a metal suchas sodium, potassium, and the like in an organic solvent such asmethanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,and the like optionally heated, optionally heated with microwaveirradiation to provide a compound of the formula (20). A compound of theformula (20) is reacted with a suitably substituted compound of theformula (2), a known compound or compound prepared by known methods, inthe presence of an acid such as hydrochloric acid, sulfuric acid,trifluoroacetic acid, and the like, in an organic solvent such asmethanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride and the like, optionally heated, optionally heatedwith microwave irradiation to provide a compound of the formula (21).Alternatively, a compound of the formula (20) may be reacted withtrimethylsilyldiazomethane in an organic solvent such as methylenechloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like to provide a compound of the formula(21). A compound of the formula (21) is reacted with a compound of theformula (22), a known compound or compound prepared by known methods, inthe presence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in the presence ofa base such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, lithium carbonate, potassium carbonate, andthe like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethaneand the like optionally heated, optionally heated with microwaveirradiation to provide a compound of the formula (23).

A compound of the formula (24), a known compound or compound prepared byknown methods, is reacted with a suitably substituted compound of theformula (2), a known compound or compound prepared by known methods, inthe presence of an acid such as hydrochloric acid, sulfuric acid,trifluoroacetic acid, and the like, in an organic solvent such asmethanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride and the like, optionally heated, optionally heatedwith microwave irradiation to provide a compound of the formula (25).Alternatively, a compound of the formula (24) may be reacted withtrimethylsilyldiazomethane in an organic solvent such as methylenechloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like to provide a compound of the formula(25). A compound of the formula (25) is reacted with a compound of theformula (7), a known compound or compound prepared by known methods, inthe presence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (26). Alternatively, a compound of the formula (25) isreacted with trimethylsilyl acetylene in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (27). A compound of the formula (27) is then deprotected byremoval of the trimethylsily moiety by reacting a compound of theformula (27) with a fluoride source such as tetrabutylammonium fluoride,and the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like to provide acompound of the formula (28). A compound of the formula (28) is reactedwith a compound of the formula (11), a known compound or compoundprepared by known methods wherein X is a chloride, bromide, iodide,methanesulfonate, trifluoromethanesulfonate, tosylate, and the like inthe presence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (26).

A compound of the formula (26), is reacted with a compound of theformula (22), a known compound or compound prepared by known methods, inthe presence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in the presence ofa base such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, lithium carbonate, potassium carbonate, andthe like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethaneand the like optionally heated, optionally heated with microwaveirradiation to provide a compound of the formula (29). A compound of theformula (29) is reacted with a base such as sodium hydroxide, lithiumhydroxide, potassium hydroxide, sodium carbonate, lithium carbonate,potassium carbonate, and the like, in an organic solvent such asmethanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,and the like optionally heated, optionally heated with microwaveirradiation to provide a compound of the formula (30).

A compound of the formula (31), a known compound or compound prepared byknown methods, is reacted with a suitably substituted compound of theformula (2), a known compound or compound prepared by known methods, inthe presence of an acid such as hydrochloric acid, sulfuric acid,trifluoroacetic acid, and the like, in an organic solvent such asmethanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride and the like, optionally heated, optionally heatedwith microwave irradiation to provide a compound of the formula (32).Alternatively, a compound of the formula (31) may be reacted withtrimethylsilyldiazomethane in an organic solvent such as methylenechloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like to provide a compound of the formula(32). A compound of the formula (32) is reacted with a compound of theformula (22), a known compound or compound prepared by known methods, inthe presence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in the presence ofa base such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, lithium carbonate, potassium carbonate, andthe like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethaneand the like, optionally heated, optionally heated with microwaveirradiation to provide a compound of the formula (33).

A compound of the formula (33) is reacted with hydrogen in the presenceof a catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of theformula (34). A compound of the formula (34) is reacted with sodiumnitrite in the presence of an acid such as hydrochloric acid, sulfuricacid, acetic acid, trifluoroacetic acid, and the like in an organicsolvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation. Further reaction with a compound ofthe formula (19) wherein M is a metal such as sodium, potassium, and thelike in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the likeoptionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (35). A compound of the formula (35)is reacted with a compound of the formula (7), a known compound orcompound prepared by known methods, in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (36). Alternatively, a compound of the formula (35) isreacted with trimethylsilyl acetylene in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (37). A compound of the formula (37) is then deprotected byremoval of the trimethylsily moiety by reacting a compound of theformula (37) with a fluoride source such as tetrabutylammonium fluoride,and the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like to provide acompound of the formula (38). A compound of the formula (38) is reactedwith a compound of the formula (11), a known compound or compoundprepared by known methods wherein X is a chloride, bromide, iodide,methanesulfonate, trifluoromethanesulfonate, tosylate, and the like inthe presence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (36).

A compound of the formula (39), a known compound or compound prepared byknown methods, is reacted with a compound of the formula (40) wherein PGis tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, benzoyl andthe like, in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, inan organic solvent such as N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like, toprovide a compound of the formula (41). A compound of the formula (41)is reacted with a compound of the formula (7), a known compound orcompound prepared by known methods, in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (42). Alternatively, a compound of the formula (41) isreacted with trimethylsilyl acetylene in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (43). A compound of the formula (43) is then deprotected byremoval of the trimethylsily moiety by reacting a compound of theformula (43) with an fluoride source such as tetrabutylammoniumfluoride, and the like in an organic solvent such as tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, and the like toprovide a compound of the formula (44). A compound of the formula (44)is reacted with a compound of the formula (11), a known compound orcompound prepared by known methods wherein X is a chloride, bromide,iodide, methanesulfonate, trifluoromethanesulfonate, tosylate, and thelike in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like inthe presence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (42).

A compound of the formula (42) is deprotected by a fluoride source suchas tetrabutylammounim fluoride and the like or a base such as aqueoussodium carbonate, potassium carbonate, cesium carbonate and the like, inan organic solvent such as methanol, ethanol, in an organic solvent suchas tetrahydrofuran, 1,4-dioxane, and the like to provide a compound ofthe formula (44). A compound of the formula (44) is reacted withtrifluoromethanesulfonic anhydride, in an organic solvent such astetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally in the presence of a basesuch as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, and the like, to provide a compound of the formula(45). A compound of the formula (45) is reacted with a compound of theformula (22), a known compound or compound prepared by known methods, inthe presence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in the presence ofa base such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, lithium carbonate, potassium carbonate, andthe like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethaneand the like optionally heated, optionally heated with microwaveirradiation to provide a compound of the formula (46). A compound of theformula (46) is then reacted with an acid such as hydrochloric acid,sulfuric acid, and the like, in a solvent such as water, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the likeoptionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (47). Alternatively, a compound of theformula (46) is reacted with a base such as sodium hydroxide, lithiumhydroxide, potassium hydroxide, and the like, in a solvent such aswater, methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane, and the like optionally heated, optionally heated withmicrowave irradiation to provide a compound of the formula (47).

A compound of the formula (48) is reacted with a compound of the formula(22a), a known compound or compound prepared by known methods, in thepresence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in the presence ofa base such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, lithium carbonate, potassium carbonate, andthe like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the likeoptionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (49). A compound of the formula (49)is reacted with a base such as sodium hydroxide, lithium hydroxide,potassium hydroxide, sodium carbonate, lithium carbonate, potassiumcarbonate, and the like, in an organic solvent such as methanol,ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and thelike optionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (50).

A compound of the formula (49) is reacted with a compound of the formula(51), a known compound or compound prepared by known methods, in thepresence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in the presence ofa base such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, sodium hydroxide, lithium hydroxide, potassiumhydroxide, sodium carbonate, lithium carbonate, potassium carbonate, andthe like, in an organic solvent such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the likeoptionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (52). A compound of the formula (52)is reacted with a base such as sodium hydroxide, lithium hydroxide,potassium hydroxide, sodium carbonate, lithium carbonate, potassiumcarbonate, and the like, in an organic solvent such as methanol,ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and thelike optionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (53). Alternatively, a compound of theformula (52) is reacted with hydrogen in the presence of a catalyst suchas palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis (triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like to provide a compound of theformula (54). A compound of the formula (54) is reacted with a base suchas sodium hydroxide, lithium hydroxide, potassium hydroxide, sodiumcarbonate, lithium carbonate, potassium carbonate, and the like, in anorganic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(55).

A compound of the formula (56), a known compound or compound prepared byknown methods, is first, reacted with chlorosulfonylisocyanate andtert-butanol in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like in asolvent such as methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the like, andsecond, is deprotected by treatment with an acid such as hydrogenchloride, trifluoroacetic acid, and the like in an organic solvent suchas ethyl acetate, methylene chloride and the like to provide a compoundof the formula (57). A compound of the formula (57) is reacted with acompound of the formula (58) in the presence of coupling agent such assuch as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide,N,N′-Dicyclohexylcarbodiimide,O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, and the like, in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,dichloroethane, methanol, ethanol, and the like, optionally in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-lutidine, and the like, optionally in the presence of4-N,N-dimethylaminopyridine, to provide a compound of the formula (59).

Alternatively, a compound of the formula (58) is reacted with a compoundof the formula (60) in the presence of coupling agent such as such as1-ethyl-3-(3-dimethylaminopropyl) carbodiimide,N,N′-Dicyclohexylcarbodiimide,O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, and the like, in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,dichloroethane, methanol, ethanol, and the like, optionally in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-lutidine, and the like, optionally in the presence of4-N,N-dimethylaminopyridine, to provide a compound of the formula (61).

A compound of the formula (62), a known compound or compound prepared byknown methods, is reacted with chlorosulfonylisocyanate in the presenceof aluminum trichloride in nitroethane to provide a compound of theformula (63). A compound of the formula (63) is reacted with an acidsuch as hydrochloric acid, sulfuric acid, trifluoroacetic acid, aceticacid, and the like, optionally in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,dichloroethane, methanol, ethanol, and the like, to provide a compoundof the formula (64). A compound of the formula (64) is reacted with acompound of the formula (65) in the presence of pyridine hydrochloride,optionally in an organic solvent such as tetrahydronfuran, 1,4-dioxane,dimethylformamide, methylene chloride, 1,2-dichloroethane, methanol,ethanol, and the like, optionally heated, optionally heated withmicrowave irradiation to provide a compound of the formula (66). Acompound of the formula (66) is reacted with a compound of the formula(7) a known compound or compound prepared by known methods, in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-dimethylpyridine, and the like in the presence of apalladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (67). A compound of the formula (67) is reacted with acompound of the formula (68), a known compound or compound prepared byknown methods, in the presence of coupling agent such as such as1-ethyl-3-(3-dimethylaminopropyl) carbodiimide,N,N′-Dicyclohexylcarbodiimide,O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, and the like, in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,dichloroethane, methanol, ethanol, and the like, optionally in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-lutidine, and the like, optionally in the presence of4-N,N-dimethylaminopyridine, to provide a compound of the formula (69).

A compound of the formula (70) is reacted with a compound of the formula(71), a known compound or compound prepared by known methods wherein Xis a chloride, bromide, iodide, methanesulfonate,trifluoromethanesulfonate, tosylate, and the like in the presence of abase such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, and the like, in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,1,2-dichloroethane, and the like, to provide a compound of the formula(72). A compound of the formula (72) is reacted with a base such assodium hydroxide, lithium hydroxide, potassium hydroxide, sodiumcarbonate, lithium carbonate, potassium carbonate, and the like, in anorganic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(73).

A compound of the formula (74) is reacted with a compound of the formula(75), a known compound or compound prepared by known methods wherein Xis a chloride, bromide, iodide, methanesulfonate,trifluoromethanesulfonate, tosylate, and the like in the presence of abase such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, and the like, in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,1,2-dichloroethane, and the like, to provide a compound of the formula(76). A compound of the formula (76) is then reacted with an acid suchas hydrochloric acid, sulfuric acids, and the like, in a solvent such aswater, methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran,1,4-dioxane, and the like optionally heated, optionally heated withmicrowave irradiation to provide a compound of the formula (77).Alternatively, a compound of the formula (76) is reacted with a basesuch as sodium hydroxide, lithium hydroxide, potassium hydroxide, andthe like, in a solvent such as water, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the likeoptionally heated, optionally heated with microwave irradiation toprovide a compound of the formula (77).

A compound of the formula (78), a known compound or compound prepared byknown methods, is reacted with sodium nitrite in the presence of an acidsuch as hydrochloric acid, sulfuric acid, tetrafluoroboric acid, and thelike, optionally in a solvent such as water, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the like,followed by reaction with sodium azide in a solvent such as water,methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,and the like to provide a compound of the formula (79). A compound ofthe formula (79) is reacted with a compound of the formula (80), a knowncompound or compound prepared by known methods, in the presence of acatalyst such as sodium ascorbate and copper sulfate and the like, in anorganic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (81). A compound of the formula (81) is reacted with acompound of the formula (7), a known compound or compound prepared byknown methods, in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like inthe presence of a palladium catalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (82). A compound of the formula (82) is reacted with a basesuch as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodiumcarbonate, lithium carbonate, potassium carbonate, and the like, in anorganic solvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(83).

A compound of the formula (84), a known compound or a compound preparedby known methods, is reacted with a compound of the formula (7), a knowncompound or a compound prepared by known methods, in the presence of abase such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, and the like, in the presence of a palladiumcatalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (85). Alternatively, a compound of the formula (84) isreacted with trimethylsilyl acetylene in the presence of a base such astriethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine,and the like in the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (86). A compound of the formula (86) is then deprotected byremoval of the trimethylsily moiety by reacting a compound of theformula (86) with an fluoride source such as tetrabutylammoniumfluoride, and the like in an organic solvent such as tetrahydrofuran,1,4-dioxane, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, and the like to provide a compound of the formula(87). Alternatively, a compound of the formula (86) is reacted withhydrogen fluoride in the presence of a base such as pyridine,2,6-dimethylpyridine, triethyl amine, and the like, optionally in asolvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride,1,2-dichloroethane, N, N-dimethylformamide, and the like to provide acompound of the formula (87). Alternatively, a compound of the formula(86) is reacted with a base such as aqueous sodium hydroxide, potassiumhydroxide, lithium hydroxide and the like, in a solvent such astetrahydrofuran, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, N,N-dimethylformamide, and the like, optionally heated, optionally heatedwith microwave irradiation to provide a compound of the formula (87). Acompound of the formula (87) is reacted with a compound of the formula(11), a known compound or compound prepared by known methods wherein Xis a leaving group such as chloride, bromide, iodide, methanesulfonate,trifluoromethanesulfonate, tosylate, and the like in the presence of abase such as triethylamine, diisopropylethylamine, pyridine,2,6-dimethylpyridine, and the like in the presence of a palladiumcatalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,methylene chloride, 1,2-dichloroethane, and the like, optionally heated,optionally heated with microwave irradiation to provide a compound ofthe formula (85).

A compound of the formula (88), a known compound or compound prepared byknown methods, is reacted with a compound of the formula (89), a knowncompound or compound prepared by known means, in the presence ofcoupling agent such as such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-Dicyclohexylcarbodiimide,O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate,Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, and the like, in an organic solvent such astetrahydronfuran, 1,4-dioxane, dimethylformamide, methylene chloride,dichloroethane, methanol, ethanol, and the like, optionally in thepresence of a base such as triethylamine, diisopropylethylamine,pyridine, 2,6-lutidine, and the like, optionally in the presence of4-N,N-dimethylaminopyridine, to provide a compound of the formula (90).A compound of the formula (90) is reacted with a base such as sodiumhydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate,lithium carbonate, potassium carbonate, and the like, in an organicsolvent such as methanol, ethanol, N, N-dimethylformamide,tetrahydrofuran, 1,4-dioxane, and the like optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(91). Alternatively, a compound of the formula (90) is reacted with anacid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, andthe like, optionally in the presence of a solvent such as methanol,ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, methylenechloride and the like optionally heated, optionally heated withmicrowave irradiation to provide a compound of the formula (91).

A compound of the formula (26), a known compound or compound prepared byknown methods, is reacted with a compound of the formula (92), a knowncompound or a compound prepared by known methods, in the presence of abase such as potassium phosphate, cesium carbonate, potassium carbonatesodium carbonate, sodium tert-butoxide and the like in the presence of acopper catalyst such as copper iodide and the like, or a palladiumcatalyst such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon,bis(acetonitrile)dichloropalladium(II), and the like, in an organicsolvent such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane,toluene, 1,2-dichloroethane, and the like, optionally heated, optionallyheated with microwave irradiation to provide a compound of the formula(93).

The examples provided below provide representative methods for preparingexemplary compounds of the present invention. The skilled practitionerwill know how to substitute the appropriate reagents, starting materialsand purification methods known to those skilled in the art, in order toprepare the compounds of the present invention.

¹H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%)and mass spectral data were determined with a Waters Alliance 2695HPLC/MS (Waters Symmetry C18, 4.6×75 mm, 3.5 μm) with a 2996 diode arraydetector from 210-400 nm.

EXAMPLES

Examples 1-177 provide a method for preparing representative compound offormula (I). The skilled practitioner will know how to substitute theappropriate reagents, starting materials and purification methods knownto those skilled in the art, in order to prepare additional compounds ofthe present invention. Preparative HPLC purification utilizes a gradientof 5-95% Acetonitrile in water (with 0.1% trifluoroacetic acid) over 15minutes.

Example 1: Synthesis of3-(3-methylsulfamoyl-phenylethynyl)-2-pyrrol-1-yl-benzoic acid

2-Amino-3-bromo-benzoic acid methyl ester: 2-Amino-3-bromo-benzoic acid(5 g, 23 mmol) was dissolved in methanol (30 mL), concentrated sulfuricacid (1 mL) was added dropwise and the reaction mixture was refluxed at80° C. for 24 hours, allowed to cool to ambient temperature and thenconcentrated at reduced pressure. The residue was diluted by water (10mL) and basified with saturated sodium bicarbonate solution, extractedby ethyl acetate (20 mL×3). The organic layer was dried (anhydrousmagnesium sulfate), concentrated and purified by column chromatographythrough a silica gel cartridge (80 g) eluting with ethyl acetate/hexane(10%) to give the product as a colorless oil (5 g, 95%).

3-Bromo-2-pyrrol-1-yl-benzoic acid methyl ester.2,5-Dimethoxytetrahydrofuran (1.7 g, 13 mmol) and 4-chloropyridine HClsalt (2 g, 13 mmol) were mixed in anhydrous 1,4-dioxane (30 mL) andstirred at room temperature for 15 minutes. To the solution was added2-amino-3-bromo-benzoic acid methyl ester (3 g, 13 mmol) and thereaction mixture was refluxed at 120° C. for 2 hours. After cooling toambient temperature, the crude mixture was filtered through celite andwashed with ethyl acetate. The filtrate was concentrated and purified bycolumn chromatography through a silica gel cartridge (80 g) eluting withethyl acetate/hexane (10%-20%) to give the product as a white solid (3.2g, 87%).

3-Ethynyl-2-pyrrol-1-yl-benzoic acid methyl ester. To a pressure flaskwas loaded a mixture of 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester(4 g, 14.2 mmol), Pd(PPh₃)₂Cl₂ (501 mg, 0.71 mmol) and CuI (270 mg, 1.42mmol) in triethylamine (40 mL), the mixture was degassed with N₂ for 10minutes, trimethylsilylacetylene (10 mL) was added and the mixture wasfurther degassed for 3 minutes. The flask was sealed with a PTFE plugand heated at 86° C. for 17 hour. After cooling to ambient temperature,the crude mixture was filtered through celite and washed withdichloromethane. The filtrate was concentrated and purified by columnchromatography through a silica gel cartridge (80 g) eluting with ethylacetate/hexane (5%-20%) to give a solid intermediate. The solidintermediate was dissolved in tetrahedrofuran (20 mL),tetrabutylammonium fluoride (1 N in THF, 20 mL, 20 mmol) was added andthe reaction mixture was stirred for 10 minutes and concentrated. Theresidue was purified by column chromatography through a silica gelcartridge (80 g) eluting with ethyl acetate/hexane (10-20%) to give theproduct as a white solid (1.7 g, 53% for 2 steps)

3-(3-Methylsulfamoyl-phenylethynyl)-2-pyrrol-1-yl-benzoic acid. Amixture of 3-ethynyl-2-pyrrol-1-yl-benzoic acid methyl ester (40 mg,0.18 mmol), 3-bromo-N-methyl-benzenesulfonamide (90 mg, 0.36 mmol),palladium tetrakis-triphenylphosphine (21 mg, 0.018 mmol) and copperiodide (6.8 mg, 0.036 mmol), potassium carbonate (50 mg, 0.36 mmol) in1,2-dimethoxyethane/water (1 mL/0.2 mL) was degassed with N₂ for 5minutes and then heated at 60° C. for 4 hours. After cooling to ambienttemperature, the crude mixture was filtered through celite and washedwith dichloromethane. The filtrate was concentrated and purified bypreparative thin layered chromatography eluting with ethylacetate/hexane (30%) to give the ester intermediate. To the esterintermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodiumhydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution wasstirred at room temperature for 18 hours. 1 N hydrochloric acid aqueoussolution was added dropwise until pH=1 and the reaction mixture waspurified through preparative HPLC to give 19 mg (28% for 2 steps) of thepure product as a white solid. ¹H NMR (CDCl₃) δ 7.87 (dd, J=7.8, 1.6 Hz,1H), 7.82-7.72 (m, 3H), 7.49-7.30 (m, 3H), 6.88 (t, J=2.2 Hz, 2H), 6.34(t, J=2.2 Hz, 2H), 2.6 (s, 3H). MS (ESI) m/z 380.9 (M+1)⁺.

Example 2: Synthesis of 3-(1H-indol-3-ylethynyl)-2-pyrrol-1-yl-benzoicacid

3-(1H-Indol-3-ylethynyl)-2-pyrrol-1-yl-benzoic acid was prepared by thesame procedure as example 1. ¹H NMR (CDCl₃) δ 7.87 (dd, J=7.8, 1.6 Hz,1H), 7.82-7.72 (m, 3H), 7.49-7.30 (m, 3H), 6.88 (t, J=2.2 Hz, 2H), 6.34(t, J=2.2 Hz, 2H), 2.6 (s, 3H). MS (ESI) m/z 380.9 (M+1)⁺.

Example 3: Synthesis of3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.84 (dd, J=1.6, 7.8 Hz, 1H), 7.74 (dd, J=1.5, 7.6 Hz, 1H), 7.44 (t,J=7.8 Hz, 1H), 7.28-7.08 (m, 4H), 6.88 ((t, J=2.1 Hz, 2H), 6.33 (t,J=2.1 Hz, 2H), 2.65 (s, 3H). MS (ESI) m/z 380.9 (M+1)⁺.

Example 4: Synthesis of2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid

2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.97-7.82 (m, 3H), 7.75 (d, J=8.8 Hz, 1H), 7.56-7.38 (m, 3H), 6.89 (t,J=2.1 Hz, 2H), 6.35 (t, J=2.1 Hz, 2H). MS (ESI) m/z 366.9 (M+1)⁺.

Example 5: Synthesis of3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.84 (dd, J=1.6, 7.8 Hz, 1H), 7.82-7.72 (m, 3H), 7.50-7.25 (m, 3H),6.88 ((t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H). MS (ESI) m/z 330.9(M+1)⁺.

Example 6: Synthesis of3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=8.24 (s, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.92-7.83 (m, 2H), 7.74-7.64 (m,2H), 7.51-7.43 (m, 2H), 6.85 (t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H).MS (ESI) m/z 328.0 (M+1)⁺.

Example 7: Synthesis of3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=8.19 (br. s., 1H), 8.03 (br. s., 1H), 7.90 (d, J=7.7 Hz, 1H), 7.75 (d,J=7.5 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.31-7.28 (m, 1H), 6.86 (t, J=2.1Hz, 2H), 6.34 (t, J=2.1 Hz, 2H). MS (ESI) m/z 305.0 (M+1)⁺.

Example 8: Synthesis of3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=8.02 (br. S., 1H), 7.85 (dd, J=1.8, 7.8 Hz, 1H), 7.78 (dd, J=1.5, 7.7Hz, 1H), 7.70-7.59 (m, 3H), 7.46 (t, J=7.9 Hz, 1H), 7.12 (d, J=8.2 Hz,1H), 6.93 (t, J=2.1 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H). MS (ESI) m/z 328.0(M+1)⁺.

Example 9: Synthesis of3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid

3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid: To a pressure tube was added a mixture of3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester (50 mg, 0.18 mmol),1-(3-ethynyl-phenyl)-3,3-dimethyl-azetidin-2-one (71 mg, 0.28 mmol),Pd(PPh₃)₂Cl₂ (12.6 mg, 0.018 mmol) and CuI (6.9 mg, 0.036 mmol) intriethylamine (1 mL). The mixture was degassed with N₂ for 10 minutesand then heated at 90° C. for 17 hours. After cooling to ambienttemperature, the crude mixture was filtered through celite and washedwith dichloromethane. The filtrate was concentrated and purified bycolumn chromatography through preparative thin layer chromatographyeluting with ethyl acetate/hexane (30%) to give a solid intermediate. Tothe solid intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) wasadded sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and thesolution was stirred at room temperature for 18 hours. 1 N hydrochloricacid aqueous solution was added dropwise until pH=1 and the reactionmixture was purified through preparative HPLC to give 12 mg (17% for 2steps) of the pure product as a yellow solid. ¹H NMR (300 MHz, CDCl₃)δ=7.85 (dd, J=1.6, 7.8 Hz, 1H), 7.74 (dd, J=1.6, 7.8 Hz, 1H), 7.53-7.35(m, 2H), 7.34-7.22 (m, 1H), 7.15 (t, J=5.0 Hz, 1H), 7.05 (d, J=7.6 Hz,1H), 6.89 (t, J=2.1 Hz, 2H), 6.35 (t, J=2.1 Hz, 2H), 3.44 (s, 2H), 2.56(s, 6H). MS (ESI) m/z 385.1 (M+1)⁺.

Example 10: Synthesis of3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoicacid

3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoicacid was isolated as a second product in purifying example 9. ¹H NMR(300 MHz, CDCl₃) δ=7.82 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.42(t, J=7.8 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 6.88 (t, J=2.1 Hz, 2H),6.75-6.58 (m, 3H), 6.33 (t, J=2.1 Hz, 2H), 3.22 (s, 2H), 1.30 (s, 6H).MS (ESI) m/z 403.1 (M+1)⁺.

Example 11: Synthesis of3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, DMSO)δ=13.1 (br. s., 1H), 9.15 (d, J=1.5 Hz, 1H), 8.12-8.04 (m, 2H),7.95-7.89 (m, 2H), 7.82 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 6.97(t, J=2.2 Hz, 2H), 6.30 (t, J=2.2 Hz, 2H). MS (ESI) m/z 328.9 (M+1)⁺.

Example 12: Synthesis of3-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.94 (dd, J=1.6, 7.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.81 (dd, J=1.5, 7.9Hz, 1H), 7.76-7.70 (m, 1H), 7.58-7.50 (m, 2H), 7.07 (t, J=6.9 Hz, 1H),6.89 (t, J=2.1 Hz, 2H), 6.40 (t, J=2.1 Hz, 2H). MS (ESI) m/z 328.0(M+1)⁺.

Example 13: Synthesis of3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=8.14 (d, J=9.1 Hz, 1H), 8.03 (dd, J=1.5, 7.9 Hz, 1H), 7.89 (dd, J=1.6,7.8 Hz, 1H), 7.81 (d, J=4.1 Hz, 1H), 7.66-7.56 (m, 2H), 7.38-7.30 (m,2H), 6.89 (t, J=2.0 Hz, 2H), 6.41 (t, J=2.0 Hz, 2H). MS (ESI) m/z 328.0(M+1)⁺.

Example 14: Synthesis of2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoicacid

2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoicacid was prepared by the same procedure as example 1. ¹H NMR (300 MHz,CDCl₃) δ=8.15 (br. s., 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.74 (dd, J=1.6,7.6 Hz, 1H), 7.67 (dd, J=1.6, 7.9 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H),7.31-7.23 (m, 1H), 6.83 (t, J=2.2 Hz, 2H), 6.46-6.31 (m, 1H), 6.27 (t,J=2.2 Hz, 2H). MS (ESI) m/z 328.0 (M+1)⁺.

Example 15: Synthesis of3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.81 (dt, J=1.5, 7.8 Hz, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.22-7.07 (m,3H), 6.94 (t, J=2.2 Hz, 2H), 6.43 (d, J=3.2 Hz, 2H), 6.35 (t, J=2.2 Hz,2H), 3.79 (s, 3H). MS (ESI) m/z 341.0 (M+1)⁺.

Example 16: Synthesis of3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.87-7.55 (m, 3H), 7.53-7.40 (m, 1H), 7.27-7.19 (m, 2H), 7.05 (d,J=2.9 Hz, 1H), 7.00-6.85 (m, 2H), 6.46 (d, J=2.9 Hz, 1H), 6.40-6.25 (m,2H), 3.78 (s, 3H). MS (ESI) m/z 341.0 (M+1)⁺.

Example 17: Synthesis of3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.90 (dd, J=1.6, 7.8 Hz, 1H), 7.82-7.75 (m, 3H), 7.52-7.41 (m, 2H),7.32-7.28 (m, 2H), 6.91 (t, J=2.1 Hz, 2H), 6.40 (t, J=2.2 Hz, 2H). MS(ESI) m/z 344.0 (M+1)⁺.

Example 18: Synthesis of3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃) δ=8.24 (br.s., 1H), 7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.83 (dd, J=1.6, 7.8 Hz, 1H),7.62 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.35-7.26 (m, 1H), 7.18(t, J=2.8 Hz, 1H), 7.04 (t, J=7.7 Hz, 1H), 6.97 (t, J=2.2 Hz, 2H),6.56-6.43 (m, 3H). MS (ESI) m/z 327.0 (M+1)⁺.

Example 19: Synthesis of3-{2-[2-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[2-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, DMSO)δ=7.81 (dd, J=1.6, 7.8 Hz, 1H), 7.74 (dd, J=1.4, 7.6 Hz, 1H), 7.60-7.34(m, 3H), 7.30-7.19 (m, 2H), 6.87 (t, J=2.2 Hz, 2H), 6.20 (t, J=2.2 Hz,2H), 5.18 (t, J=5.6 Hz, 1H), 4.45 (d, J=5.0 Hz, 2H). MS (ESI) m/z 317.9(M+1)⁺.

Example 20: Synthesis of3-{2-[4-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[4-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.82 (dd, J=1.6, 7.8 Hz, 1H), 7.73 (dd, J=1.6, 7.8 Hz, 1H), 7.42 (t,J=7.8 Hz, 1H), 7.35-7.27 (m, 4H), 6.88 (t, J=2.1 Hz, 2H), 6.33 (t, J=2.1Hz, 2H), 4.64 (s, 2H). MS (ESI) m/z 317.9 (M+1)⁺.

Example 21: Synthesis of2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(4-methylphenyl)ethynyl]benzoicacid

3-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid: A mixture of2-amino-3-bromo-benzoic acid (2 g, 9.26 mmol) in hexane-2,5-dione (20mL) was heated at 100° C. for 3 days, allowed to cool to ambienttemperature and then partitioned between water and ethyl acetate. Theorganic layer was dried (anhydrous magnesium sulfate), concentrated andpurified by HPLC to give the product as a solid (1.6 g, 59%).

3-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid methyl ester. To asolution of 3-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid (1.4 g,4.8 mmol) in ether (30 mL) and methanol (10 mL) at 0° C. was addedtrimethylsilyldiazomethane (2 M in hexane, 4.8 mL, 9.5 mmol) dropwise.After addition the reaction mixture was stirred at room temperature for30 minutes. Acetic acid (0.2 mL) was added to quench the reaction andthe solution was concentrated and purified by column chromatographythrough eluting with ethyl acetate/hexane (10%) to give the desiredproduct 3-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid methyl esteras a solid.

2-(2,5-dimethyl-pyrrol-1-yl)-3-p-tolylethynyl-benzoic acid: To apressure tube was loaded a mixture of3-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid methyl ester (40 mg,0.13 mmol), 1-ethynyl-4-methyl-benzene (75 mg, 0.65 mmol), Pd(PPh₃)₂Cl₂(9.1 mg, 0.013 mmol) and CuI (5 mg, 0.026 mmol) in triethylamine (1 mL).The mixture was degassed with N₂ for 10 minutes and then heated at 90°C. for 17 hours. After cooling to ambient temperature, the crude mixturewas filtered through celite and washed with dichloromethane. Thefiltrate was concentrated and purified by column chromatography throughpreparative thin layer chromatography eluting with ethyl acetate/hexane(20%) to give a solid. To solid in tetrahydrofuran/methanol (1 mL/0.2mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol)and the solution was stirred at room temperature for 18 hours. 1 Nhydrochloric acid aqueous solution was added dropwise until pH=1 and thereaction mixture was purified through preparative HPLC to give 6 mg (14%for 2 steps) of the pure product as a brown solid. ¹H NMR (300 MHz,CDCl₃) δ=8.07 (dd, J=1.8, 7.9 Hz, 1H), 7.80 (dd, J=1.5, 7.9 Hz, 1H),7.52 (t, J=7.8 Hz, 1H), 7.26-7.07 (m, 4H), 5.98 (s, 2H), 3.98 (s, 2H),2.33 (s, 3H), 1.97 (s, 6H). MS (ESI) m/z 330.0 (M+1)⁺.

Example 22: Synthesis of2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoicacid

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoicacid was prepared by the same procedure as example 21. ¹H NMR (300 MHz,CDCl₃) δ=8.06 (dd, J=1.5, 7.6 Hz, 1H), 7.80 (dd, J=1.5, 7.6 Hz, 1H),7.52 (t, J=7.8 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.91-6.70 (m, 3H), 5.98(s, 2H), 5.61 (br. s., 1H), 1.97 (s, 6H). MS (ESI) m/z 332.1 (M+1)⁺.

Example 23: Synthesis of3-[2-(2,3-dihydro-1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(2,3-dihydro-1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. MS (ESI) m/z 332.1(M−H₂O)⁺.

Example 24: Synthesis of3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. MS (ESI) m/z 292.0(M+1)⁺.

Example 25: Synthesis of3-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoicacid

3-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoicacid was prepared by the same procedure as example 1. MS (ESI) m/z 306.1(M+1)⁺.

Example 26: Synthesis of3-[2-(1-methyl-1H-imidazol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-methyl-1H-imidazol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. MS (ESI) m/z 292.1(M+1)⁺.

Example 27: Synthesis of3-[2-(1-methyl-1H-imidazol-2-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-methyl-1H-imidazol-2-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. MS (ESI) m/z 292.1(M+1)⁺.

Example 28: Synthesis of2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-5-yl)ethynyl]benzoic acid

2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-5-yl)ethynyl]benzoic acid wasprepared by the same procedure as example 1. MS (ESI) m/z 295.0 (M+1)⁺.

Example 29: Synthesis of2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid wasprepared by the same procedure as example 1. MS (ESI) m/z 295.0 (M+1)⁺.

Example 30: Synthesis of2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-6-yl}ethynyl)benzoicacid

2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-6-yl}ethynyl)benzoicacid was prepared by the same procedure as example 1. MS (ESI) m/z 328.0(M+1)⁺.

Example 31: Synthesis of3-{2-[3-(2-hydroxypropan-2-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid

3-{2-[3-(2-hydroxypropan-2-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid was prepared by the same procedure as example 1. ¹H NMR (300 MHz,CDCl₃) δ=7.84 (dd, J=1.6, 7.6 Hz, 1H), 7.74 (dd, J=1.6, 7.8 Hz, 1H),7.50-7.41 (m, 2H), 7.34-7.17 (m, 3H), 6.89 (t, J=2.1 Hz, 2H), 6.34 (t,J=2.1 Hz, 2H), 1.56 (s, 6H). MS (ESI) m/z 346.1 (M+1)⁺.

Example 32: Synthesis of3-(3-hydroxy-4-methylpent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(3-hydroxy-4-methylpent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.87 (dd, J=1.5, 7.9 Hz, 1H), 7.67 (dd, J=1.5, 7.6 Hz, 1H), 7.42 (t,J=7.7 Hz, 1H), 6.76 (t, J=2.1 Hz, 2H), 6.28 (t, J=2.1 Hz, 2H), 4.22 (dd,J=5.7, 12.2 Hz, 1H), 2.01-1.73 (m, 1H), 0.89 (d, J=6.7 Hz, 6H). MS (ESI)m/z 266.1 (M−H₂O)⁺.

Example 33: Synthesis of3-(3-hydroxy-3-phenylprop-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(3-hydroxy-3-phenylprop-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.84 (d, J=7.5 Hz, 1H), 7.68 (dd, J=1.6, 7.8 Hz, 1H), 7.44-7.19 (m,6H), 6.83 (t, J=2.2 Hz, 2H), 6.31 (t, J=2.2 Hz, 2H), 5.48 (s, 1H). MS(ESI) m/z 300.0 (M−H₂O)⁺.

Example 34: Synthesis of2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoicacid

2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoicacid was prepared by the same procedure as example 1. ¹H NMR (300 MHz,DMSO) δ=12.14 (br. s., 1H), 8.26 (d, J=3.5 Hz, 1H), 7.79-7.70 (m, 3H),7.68 (dd, J=1.6, 7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.13 (dd, J=4.7,7.9 Hz, 1H), 6.92 (t, J=2.2 Hz, 2H), 6.24 (t, J=2.2 Hz, 2H). MS (ESI)m/z 328.0 (M+H)⁺.

Example 35: Synthesis of3-[2-(1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃) δ=7.85-7.79(m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.24-7.18 (m, 2H),7.11 (t, J=7.9 Hz, 1H), 6.95 (t, J=2.2 Hz, 2H), 6.51-6.47 (m, 1H), 6.36(t, J=2.2 Hz, 2H). MS (ESI) m/z 327.0 (M+H)⁺.

Example 36: Synthesis of2-(1H-pyrrol-1-yl)-3-(2-{[1,2,4]triazolo[1,5-a]pyridin-7-yl}ethynyl)benzoicacid

2-(1H-pyrrol-1-yl)-3-(2-{[1,2,4]triazolo[1,5-a]pyridin-7-yl}ethynyl)benzoicacid was prepared by the same procedure as example 1. ¹H NMR (300 MHz,CDCl₃) δ=8.51 (d, J=7.0 Hz, 1H), 8.38 (s, 1H), 7.93 (dd, J=1.6, 7.8 Hz,1H), 7.79 (d, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.49 (t, J=7.9 Hz, 1H),6.93-6.87 (m, 3H), 6.37 (t, J=2.1 Hz, 2H). MS (ESI) m/z 329.1 (M+H)⁺.

Example 37: Synthesis of3-{2-[3-(dimethylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid

3-{2-[3-(dimethylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid was prepared by the same procedure as example 1. ¹H NMR (300 MHz,CDCl₃) δ=7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.82-7.64 (m, 3H), 7.50-7.42 (m,3H), 6.89 (t, J=2.1 Hz, 2H), 6.34 (t, J=2.1 Hz, 2H), 2.76 (s, 6H). MS(ESI) m/z 395.1 (M+H)⁺.

Example 38: Synthesis of3-[2-(3-fluoro-5-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(3-fluoro-5-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.84 (dd, J=1.6, 7.8 Hz, 1H), 7.72 (dd, J=1.6, 7.8 Hz, 1H), 7.43 (t,J=7.8 Hz, 1H), 6.87 (t, J=2.2 Hz, 2H), 6.64-6.47 (m, 3H), 6.33 (t, J=2.2Hz, 2H). MS (ESI) m/z 322.0 (M+H)⁺.

Example 39: Synthesis of3-{2-[3-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[3-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.83 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.9 Hz,1H), 7.36-7.23 (m, 4H), 6.89 (t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H),4.63 (s, 2H). MS (ESI) m/z 318.0 (M+H)⁺.

Example 40: Synthesis of3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=8.15 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.75 (dd,J=1.6, 7.8 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.25-7.22 (m, 1H), 6.87 (t,J=2.2 Hz, 2H), 6.34 (t, J=2.2 Hz, 2H). MS (ESI) m/z 305.1 (M+H)⁺.

Example 41: Synthesis of3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. MS (ESI) m/z 328.1 (M+H)⁺.

Example 42: Synthesis of3-[2-(1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃) δ=8.03 (s,1H), 7.82 (dd, J=1.6, 7.8 Hz, 1H), 7.79-7.73 (m, 2H), 7.47-7.40 (m, 2H),7.34-7.28 (m, 1H), 6.92 (t, J=2.2 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H). MS(ESI) m/z 328.1 (M+H)⁺.

Example 43: Synthesis of3-[2-(1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 1. ¹H NMR (300 MHz, DMSO) δ=11.29 (br.s., 1H), 7.79 (dd, J=1.5, 7.7 Hz, 1H), 7.69 (dd, J=1.6, 7.8 Hz, 1H),7.51 (t, J=7.6 Hz, 2H), 7.44 (t, J=2.8 Hz, 1H), 7.37 (s, 1H), 6.95-6.90(m, 3H), 6.46-6.42 (m, 1H), 6.24 (t, J=2.2 Hz, 2H). MS (ESI) m/z 327.0(M+H)⁺.

Example 44: Synthesis of3-[2-(4-methylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(4-methylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.88 (dd, J=1.6, 7.8 Hz, 1H), 7.77 (dd, J=1.5, 7.6 Hz, 1H), 7.47 (t,J=7.8 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 2H), 6.88 (t,J=2.2 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H), 2.34 (s, 3H). MS (ESI) m/z 302.0(M+H)⁺.

Example 45: Synthesis of3-[2-(3,5-difluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(3,5-difluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.95 (d, J=8.0 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.8 Hz,1H), 6.87-6.74 (m, 5H), 6.39 (t, J=2.1 Hz, 2H). MS (ESI) m/z 323.2(M−H₂O)⁺.

Example 46: Synthesis of3-{2-[3-(difluoromethoxy)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[3-(difluoromethoxy)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 1. ¹H NMR (300 MHz, CDCl₃)δ=7.92 (dd, J=1.8, 7.8 Hz, 1H), 7.78 (dd, J=1.6, 7.8 Hz, 1H), 7.47 (t,J=7.8 Hz, 1H), 7.33-7.22 (m, 1H), 7.19-7.14 (m, 1H), 7.10-7.04 (m, 2H),6.86 (t, J=2.2 Hz, 2H), 6.49 (t, J=73.6 Hz, 1H), 6.37 (t, J=2.2 Hz, 2H).MS (ESI) m/z 354.1 (M+H)⁺.

Example 47: Synthesis of 3-ethynyl-2-(1H-pyrrol-1-yl)benzoic acid

To 3-ethynyl-2-pyrrol-1-yl-benzoic acid methyl ester (50 mg, 0.22 mmol)in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxidesolution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirredat room temperature for 18 hours. 1 N hydrochloric acid aqueous solutionwas added dropwise until pH=1 and the reaction mixture was purifiedthrough preparative HPLC to give 43 mg (92%) of the pure product as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ=7.70-7.58 (m, 2H), 7.39 (t, J=7.8Hz, 1H), 6.80 (t, J=2.1 Hz, 1H), 6.31 (t, J=2.1 Hz, 2H), 3.65 (s, 2H).MS (ESI) m/z 212.0 (M+H)⁺.

Example 48: Synthesis of3-(3-amino-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(3-amino-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, DMSO)δ=8.49 (br. s., 2H), 7.76 (dd, J=1.8, 7.6 Hz, 1H), 7.66 (dd, J=1.8, 7.6Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 6.82 (t, J=2.2 Hz, 2H), 6.17 (t, J=2.2Hz, 2H), 1.41 (s, 6H). MS (ESI) m/z 269.0 (M+H)⁺.

Example 49: Synthesis of3-(3,3-dimethylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(3,3-dimethylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.78 (dd, J=1.2, 7.6 Hz, 1H), 7.61 (dd, J=1.2, 7.6 Hz, 1H), 7.35 (t,J=7.8 Hz, 1H), 6.76 (t, J=1.9 Hz, 2H), 6.26 (t, J=1.9 Hz, 2H), 1.14 (s,9H). MS (ESI) m/z 268.2 (M+H)⁺.

Example 50: Synthesis of2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 21. ¹H NMR (300 MHz, CDCl₃)δ=8.04 (dd, J=1.6, 7.8 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.9Hz, 1H), 7.36-7.21 (m, 5H), 5.97 (s, 2H), 1.97 (s, 6H). MS (ESI) m/z316.0 (M+H)⁺.

Example 51: Synthesis of2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid

5-Bromo-4-pyrrol-1-yl-nicotinic acid methyl ester was prepared in thesame manner as 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester.

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 9 starting from5-bromo-4-pyrrol-1-yl-nicotinic acid methyl ester. MS (ESI) m/z 307.0(M+H)⁺.

Example 52: Synthesis of5-(2-phenylethynyl)-4-(1H-pyrrol-1-yl)pyridine-3-carboxylic acid

5-(2-phenylethynyl)-4-(1H-pyrrol-1-yl)pyridine-3-carboxylic acid wasprepared by the same procedure as example 51. MS (ESI) m/z 289.0 (M+H)⁺.

Example 53: Synthesis of3-[2-(1-aminocyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidtrifluoroacetic acid

3-[2-(1-aminocyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidtrifluoroacetic acid was prepared by the same procedure as example 9. ¹HNMR (300 MHz, CDCl₃) δ=7.87 (dd, J=1.5, 7.9 Hz, 1H), 7.68 (dd, J=1.6,7.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 6.77 (t, J=2.2 Hz, 2H), 6.25 (t,J=2.2 Hz, 2H), 3.22 (br. s., 2H), 2.00-1.95 (m, 2H), 1.79-1.51 (m, 5H),1.48-1.05 (m, 3H). MS (ESI) m/z 292.1 (M−H₂O)⁺.

Example 54: Synthesis of3-[2-(1-hydroxycyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(1-hydroxycyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.78 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.36 (t, J=7.8 Hz,1H), 6.76 (t, J=2.0 Hz, 2H), 6.23 (t, J=2.0 Hz, 2H), 1.84-1.71 (m, 2H),1.62-1.10 (m, 8H). MS (ESI) m/z 292.1 (M−H₂O)⁺.

Example 55: Synthesis of3-(4-ethyl-3-hydroxyoct-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(4-ethyl-3-hydroxyoct-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. MS (ESI) m/z 322.2(M−H₂O)⁺.

Example 56: Synthesis of3-(2-{imidazo[1,2-a]pyrazin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-{imidazo[1,2-a]pyrazin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 9. ¹H NMR (300 MHz, DMSO)δ=9.03 (s, 1H), 8.64 (s, 1H), 8.19 (s, 1H), 7.93-7.75 (m, 2H), 7.57 (dd,J=1.6, 7.8 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 6.92 (t, J=2.2 Hz, 2H), 6.24(t, J=2.2 Hz, 2H). MS (ESI) m/z 328.9 (M+H)⁺.

Example 57: Synthesis of3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.79 (dd, J=1.6, 7.8 Hz, 1H), 7.66 (dd, J=1.6, 7.8 Hz, 1H), 7.39 (t,J=7.8 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 6.90-6.71 (m, 5H), 6.30 (t, J=2.2Hz, 2H. MS (ESI) m/z 304.1 (M+H)⁺.

Example 58: Synthesis of5-chloro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-Bromo-5-chloro-2-pyrrol-1-yl-benzoic acid methyl ester was prepared inthe same manner as 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester.

5-chloro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 9 starting from3-bromo-5-chloro-2-pyrrol-1-yl-benzoic acid methyl ester. ¹H NMR (300MHz, CDCl₃) δ=7.85 (d, J=3.6 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.33-7.23(m, 2H), 7.04-6.95 (m, 2H), 6.82 (t, J=2.0 Hz, 2H), 6.36 (t, J=2.0 Hz,2H). MS (ESI) m/z 340.1 (M+H)⁺.

Example 59: Synthesis of5-chloro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

5-Chloro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 58. ¹H NMR (300 MHz, CDCl₃) δ=7.83 (d,J=2.3 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.35-7.25 (m, 5H), 6.82 (t, J=2.0Hz, 2H), 6.35 (t, J=1.8 Hz, 2H). MS (ESI) m/z 322.1 (M+H)⁺.

Example 60: Synthesis of5-fluoro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-Bromo-5-fluoro-2-pyrrol-1-yl-benzoic acid methyl ester was prepared inthe same manner as 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester.

5-Fluoro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 9 starting from3-bromo-5-fluoro-2-pyrrol-1-yl-benzoic acid methyl ester. ¹H NMR (300MHz, CDCl₃) δ=7.59 (dd, J=2.9, 8.2 Hz, 1H), 7.45 (dd, J=2.6, 7.9 Hz,1H), 7.31-7.24 (m, 2H), 7.02-6.94 (m, 2H), 6.82 (t, J=2.0 Hz, 2H), 6.35(t, J=2.0 Hz, 2H). MS (ESI) m/z 324.0 (M+H)⁺.

Example 61: Synthesis of5-fluoro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

5-fluoro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 60. ¹H NMR (300 MHz, CDCl₃) δ=7.58 (dd,J=3.1, 8.1 Hz, 1H), 7.46 (dd, J=2.9, 8.2 Hz, 1H), 7.36-7.25 (m, 5H),6.81 (t, J=2.2 Hz, 2H), 6.35 (t, J=2.1 Hz, 2H).

Example 62: Synthesis of3-(2-cyclopropylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-cyclopropylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared bythe same procedure as example 9. ¹H NMR (300 MHz, CDCl₃) δ=7.77 (dd,J=1.6, 7.8 Hz, 1H), 7.61 (dd, J=1.6, 7.8 Hz, 1H), 7.34 (t, J=7.8 Hz,1H), 6.74 (t, J=2.2 Hz, 2H), 6.26 (t, J=2.2 Hz, 2H), 1.31-1.22 (m, 1H),0.83-0.69 (m, 2H), 0.69-0.60 (m, 2H). MS (ESI) m/z 234.0 (M−H₂O)⁺.

Example 63: Synthesis of3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.77 (d, J=7.7 Hz, 1H), 7.57 (dd, J=1.6, 7.8 Hz, 1H), 7.34 (t, J=7.8Hz, 1H), 6.75 (t, J=2.2 Hz, 2H), 6.24 (t, J=2.2 Hz, 2H), 1.39 (s, 6H).MS (ESI) m/z 252.1 (M−H₂O)⁺.

Example 64: Synthesis of3-[3-(dimethylamino)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[3-(dimethylamino)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.95 (dd, J=1.6, 7.8 Hz, 1H), 7.70 (dd, J=1.6, 7.8 Hz, 1H), 7.49 (t,J=7.8 Hz, 1H), 6.78 (t, J=2.2 Hz, 2H), 6.26 (t, J=2.1 Hz, 2H), 4.01 (s,2H), 2.61 (s, 6H). MS (ESI) m/z 269.1 (M+H)⁺.

Example 65: Synthesis of3-(4-phenylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(4-phenylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared bythe same procedure as example 9. ¹H NMR (300 MHz, CDCl₃) δ=7.78 (dd,J=1.6, 7.8 Hz, 1H), 7.60 (dd, J=1.6, 7.8 Hz, 1H), 7.37-7.09 (m, 6H),6.76 (t, J=2.2 Hz, 2H), 6.28 (t, J=2.1 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H),2.55 (t, J=7.3 Hz, 2H). MS (ESI) m/z 316.1 (M+H)⁺.

Example 66: Synthesis of3-(5-hydroxypent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(5-hydroxypent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃) δ=7.77 (d,J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 6.78 (t,J=2.2 Hz, 2H), 6.30 (t, J=2.2 Hz, 2H), 3.53 (t, J=9.5 Hz, 2H), 2.40 (t,J=9.7 Hz, 2H), 1.71-1.62 (m, 2H). MS (ESI) m/z 270.1 (M+H)⁺.

Example 67: Synthesis of3-[2-(4-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(4-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.86 (dd, J=1.6, 7.8 Hz, 1H), 7.75 (dd, J=1.5, 7.9 Hz, 1H), 7.43 (t,J=7.9 Hz, 1H), 7.29-7.23 (m, 2H), 6.89-6.80 (m, 4H), 6.36 (t, J=2.2 Hz,2H), 3.80 (s, 3H). MS (ESI) m/z 318.1 (M+H)⁺.

Example 68: Synthesis of3-[2-(pyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(pyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃) δ=8.63 (d,J=6.5 Hz, 2H), 7.97 (dd, J=1.6, 7.8 Hz, 1H), 7.79 (dd, J=1.6, 7.8 Hz,1H), 7.51 (t, J=7.8 Hz, 1H), 7.44-7.40 (m, 2H), 6.78 (t, J=2.2 Hz, 2H),6.30 (t, J=2.2 Hz, 2H). MS (ESI) m/z 289.1 (M+H)⁺.

Example 69: Synthesis of3-[2-(pyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(pyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃) δ=¹H NMR(300 MHz, CDCl₃) δ=8.80-8.55 (m, 2H), 7.99-7.87 (m, 2H), 7.80-7.74 (m,1H), 7.65-7.55 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 6.86 (t, J=2.2 Hz, 2H),6.35 (t, J=2.2 Hz, 2H). MS (ESI) m/z 289.1 (M+H)⁺.

Example 70: Synthesis of3-[2-(3-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(3-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.90 (dd, J=1.7, 7.8 Hz, 1H), 7.78 (dd, J=1.6, 7.8 Hz, 1H), 7.46 (t,J=7.9 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.95-6.82 (m, 5H), 6.37 (t, J=2.2Hz, 2H), 3.80 (s, 3H). MS (ESI) m/z 318.1 (M+H)⁺.

Example 71: Synthesis of3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 9. ¹H NMR (300 MHz, CDCl₃)δ=7.88 (dd, J=1.5, 7.9 Hz, 1H), 7.75 (dd, J=1.6, 7.7 Hz, 1H), 7.44 (t,J=7.8 Hz, 1H), 7.32-7.26 (m, 2H), 7.02-6.94 (m, 2H), 6.87 (t, J=2.2 Hz,2H), 6.25 (t, J=2.2 Hz, 2H). MS (ESI) m/z 306.0 (M+H)⁺.

Example 72: Synthesis of 3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoicacid

3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by thesame procedure as example 9. ¹H NMR (300 MHz, CDCl₃) δ=7.86 (dd, J=1.5,7.9 Hz, 1H), 7.77 (dd, J=1.6, 7.8 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H),7.35-7.26 (m, 5H), 6.87 (t, J=2.1 Hz, 2H), 6.36 (t, J=2.1 Hz, 2H). MS(ESI) m/z 288.0 (M+H)⁺.

Example 73:3-{3-[benzyl(methyl)amino]prop-1-yn-1-yl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{3-[benzyl(methyl)amino]prop-1-yn-1-yl}-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 9. ¹H NMR (300 MHz, CD₃OD)δ=7.82-7.6 (m, 2H), 7.58-7.45 (m, 4H), 7.42-7.38 (m, 1H), 6.90 (d, J=3.4Hz, 2H), 6.82-6.55 (m, 1H), 6.28-6.22 (m, 2H), 4.42-4.21 (m, 2H), 4.08(m, 2H), 2.75-2.67 (m, 3H). MS (ES⁺)=345.0 (MH)⁺.

Example 74:3-[3-(1H-imidazol-1-yl)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[3-(1H-imidazol-1-yl)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acidwas prepared by the same procedure as example 9. ¹H NMR (300 MHz, CD₃OD)δ=8.89 (br. s., 1H), 8.79-8.63 (m, 1H), 8.60-8.44 (m, 1H), 8.37-8.22 (m,1H), 8.16-8.07 (m, 1H), 7.91-7.76 (m, 1H), 7.61-7.48 (m, 1H), 7.36 (d,J=7.6 Hz, 1H), 7.00 (br. s., 1H), 6.51 (d, J=12.0 Hz, 1H), 4.64 (br. s.,2H). MS (ES⁺)=291.9 (M)⁺.

Example 75: Synthesis of 3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid. A mixture of3-ethynyl-1-yl-benzoic acid methyl ester (40 mg, 0.25 mmol),4-bromo-thiazole (82 mg, 0.5 mmol), palladiumtetrakis-triphenylphosphine (29 mg, 0.025 mmol) and copper iodide (9.5mg, 0.05 mmol), potassium carbonate (69 mg, 0.5 mmol) in1,2-dimethoxyethane/water (1 mL/0.3 mL) was degassed with N₂ for 5minutes and then heated at 60° C. for 4 hours. After cooling to ambienttemperature, the crude mixture was filtered through celite and washedwith dichloromethane. The filtrate was concentrated and purified bypreparative thin layered chromatography eluting with ethylacetate/hexane (30%) to give the ester intermediate. To thisintermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodiumhydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution wasstirred at room temperature for 18 hours. 1 N hydrochloric acid aqueoussolution was added dropwise until pH=1 and the reaction mixture waspurified through preparative HPLC to give 18 mg (22% for 2 steps) of thepure product as a white solid. ¹H NMR (300 MHz, DMSO) δ=13.2 (br. s.,1H), 9.18 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.05 (t, J=1.5 Hz,1H), 7.98 (td, J=1.4, 7.8 Hz, 1H), 7.81 (td, J=1.4, 7.8 Hz, 1H), 7.57(t, J=7.8 Hz, 1H). LCMS (ESI) m/z 230.0 (M+1)⁺.

Example 76: Synthesis of3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid

3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared bythe same procedure as example 75. ¹H NMR (300 MHz, DMSO) δ=12.20 (br.s., 1H), 8.31 (dd, J=1.5, 4.7 Hz, 1H), 8.13 (dd, J=1.5, 7.9 Hz, 1H),8.05 (d, J=2.4 Hz, 1H), 7.97-7.95 (m, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.78(d, J=7.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.20 (dd, J=4.8, 7.8 Hz, 1H).LCMS (ESI) m/z 263.0 (M+1)⁺.

Example 77: Synthesis of 3-[2-(1H-indol-5-yl)ethynyl]benzoic acid

3-[2-(1H-indol-5-yl)ethynyl]benzoic acid was prepared by the sameprocedure as example 75. ¹H NMR (300 MHz, CDCl₃) δ=9.30 (br. s., 1H),8.23 (t, J=1.8 Hz, 1H), 7.98 (td, J=1.5, 7.9 Hz, 1H), 7.87 (d, J=0.9 Hz,1H), 7.72 (td, J=1.3, 7.9 Hz, 1H), 7.47-7.23 (m, 4H), 6.59-6.50 (m, 1H).LCMS (ESI) m/z 262.0 (M+1)⁺.

Example 78: Synthesis of2-amino-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid

2-Amino-3-bromo-benzoic acid methyl ester: 2-Amino-3-bromo-benzoic acid(5 g, 23 mmol) was dissolved in methanol (30 mL), concentrated sulfuricacid (1 mL) was added dropwise and the reaction mixture was refluxed at80° C. for 24 hours, allowed to cool to ambient temperature and thenconcentrated at reduced pressure. The residue was diluted by water (10mL) and basified with saturated sodium bicarbonate solution, extractedby ethyl acetate (20 mL×3). The organic layer was dried (anhydrousmagnesium sulfate), concentrated and purified by column chromatographythrough a silica gel cartridge (80 g) eluting with ethyl acetate/hexane(10%) to give the product as a colorless oil (5 g, 95%).

2-Amino-3-ethynyl-benzoic acid methyl ester: To a pressure flask wasloaded a mixture of 2-amino-3-bromo-benzoic acid methyl ester (2 g, 8.7mmol), Pd(PPh₃)₂Cl₂ (610 mg, 0.87 mmol) and CuI (331 mg, 1.74 mmol) intriethyl amine (20 mL), the mixture was degassed with N₂ for 10 minutes,trimethylsilylacetylene (4 mL) was added, and the mixture was furtherdegassed for 3 minutes. The flask was sealed with a PFTE plug and heatedat 90° C. for 5 hours. After cooling to ambient temperature, the crudemixture was filtered through celite and washed with dichloromethane andthe filtrate was concentrated and purified by column chromatographythrough a silica gel cartridge (80 g) eluting with hexane to give asolid intermediate. The solid intermediate was dissolved intetrahedrofuran (15 mL), tetrabutyl ammonium fluoride (1 N in THF, 14mL, 14 mmol) was added and the reaction mixture was stirred for 10minutes and concentrated. The residue was purified by columnchromatography through a silica gel cartridge (80 g) eluting with ethylacetate/hexane (0-20%) to give the product as a white solid (1.4 g, 86%for 2 steps).

2-amino-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid wasprepared by the same procedure as example 75 starting with2-amino-3-ethynyl-benzoic acid methyl ester. ¹H NMR (300 MHz, CDCl₃)δ=7.98-7.76 (m, 1H), 7.68-7.52 (m, 1H), 7.44 (d, J=8.5 Hz, 1H),7.35-7.30 (m, 3H), 7.25-7.14 (m, 1H), 6.77-6.48 (m, 2H).

Example 79: Synthesis of 2-amino-3-[2-(1H-indol-4-yl)ethynyl]benzoicacid

2-amino-3-[2-(1H-indol-4-yl)ethynyl]benzoic acid was prepared by thesame procedure as example 78. ¹H NMR (300 MHz, CDCl₃) δ=7.94 (td, J=1.7,7.4 Hz, 2H), 7.60 (dd, J=1.6, 7.5 Hz, 1H), 7.53 (dd, J=1.6, 7.6 Hz, 1H),7.44 (d, J=8.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.17 (t, J=8.0 Hz, 1H),6.76-6.52 (m, 3H). LCMS (ESI) m/z 278.0 (M+1)⁺.

Example 80: Synthesis of 2-amino-3-[2-(1H-indol-6-yl)ethynyl]benzoicacid

2-amino-3-[2-(1H-indol-6-yl)ethynyl]benzoic acid was prepared by thesame procedure as example 78. ¹H NMR (300 MHz, CDCl₃) δ=7.91 (dd, J=1.6,8.1 Hz, 1H), 7.72-7.44 (m, 3H), 7.41-7.17 (m, 4H), 6.64 (t, J=7.8 Hz,1H), 6.55 (d, J=3.4 Hz, 1H). LCMS (ESI) m/z 278.0 (M+1)⁺.

Example 81: Synthesis of 2-amino-3-[2-(1H-indol-5-yl)ethynyl]benzoicacid

2-amino-3-[2-(1H-indol-5-yl)ethynyl]benzoic acid was prepared by thesame procedure as example 78. LCMS (ESI) m/z 277.1 (M+1)⁺.

Example 82: Synthesis of2-amino-3-{2-[3-(hydroxymethyl)phenyl]ethynyl}benzoic acid

2-amino-3-{2-[3-(hydroxymethyl)phenyl]ethynyl}benzoic acid was preparedby the same procedure as example 78. LCMS (ESI) m/z 250.1 (M−H₂O)⁺.

Example 83: Synthesis of 2-amino-3-[2-(3-hydroxyphenyl)ethynyl]benzoicacid

2-amino-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid: To a sealed tube wasloaded a mixture of 2-amino-3-bromo-benzoic acid methyl ester (50 mg,0.22 mmol), Pd(PPh₃)₂Cl₂ (15.4 mg, 0.022 mmol) and CuI (4.2 mg, 0.022mmol) in triethyl amine (1 mL). The mixture was degassed with N₂ for 10minutes, 3-ethynyl-phenol (103 mg, 0.87 mmol) was added and the mixturedegassed with N₂ for 5 minutes. The reaction mixture was heated at 90°C. for 5 hours. After cooling to ambient temperature, the crude mixturewas filtered through celite and washed with dichloromethane. Thefiltrate was concentrated and purified by preparative thin layerchromatography eluting with ethyl acetate/hexane (30%) to give a solidintermediate. To the solid intermediate in tetrahydrofuran/methanol (1mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL,0.4 mmol) and the solution was stirred at room temperature for 18 hours.1 N hydrochloric acid aqueous solution was added dropwise until pH=1 andthe reaction mixture was purified through preparative HPLC to give 11 mg(14% for 2 steps) of the pure product as a white solid. LCMS (ESI) m/z254.1 (M+1)⁺.

Example 84: Synthesis of 2-amino-3-(2-phenylethynyl)benzoic acid

2-amino-3-(2-phenylethynyl)benzoic acid was prepared by the sameprocedure as example 83. ¹H NMR (300 MHz, CDCl₃) δ=7.93 (dd, J=1.6, 8.1Hz, 1H), 7.58-7.50 (m, 4H), 7.39-7.34 (m, 4H), 6.64 (t, J=7.6 Hz, 1H).LCMS (ESI) m/z 220.2 (M−H₂O)⁺.

Example 85: Synthesis of 2-fluoro-3-(2-phenylethynyl)benzoic acid

2-fluoro-3-(2-phenylethynyl)benzoic acid was prepared by the sameprocedure as example 83 starting with 2-fluoro-3-bromobenzoic acidmethyl ester. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (m, 1H), 7.75 (m, 1H), 7.57(m, 2H), 7.48-7.32 (m, 4H). MS m/z (M+) 240.7.

Example 86: Synthesis of2-fluoro-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid

2-fluoro-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid wasprepared by the same procedure as example 78 starting with2-fluoro-3-bromobenzoic acid methyl ester. ¹H NMR (300 MHz, CD₃OD) δ8.34(bs, 1H), 8.25 (dd, J=7.9, 1.3 Hz, 1H), 7.98-7.83 (m, 1H), 7.80-7.71 (m,2H), 7.35-7.31 (m, 1H), 7.28 (t, J=7.7 Hz, 1H). MS m/z (M+H) 281.0.

Example 87: Synthesis of2-fluoro-3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)benzoic acid

2-fluoro-3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)benzoic acid wasprepared by the same procedure as example 86. ¹H NMR (300 MHz, DMSO)δ9.21 (d, J=1.5 Hz, 1H), 8.66 (dd, J=4.6, 1.5 Hz, 1H), 8.28 (s, 1H),8.14 (d, J=4.5 Hz, 1H), 8.06-7.97 (m, 1H), 7.97-7.89 (m, 1H), 7.41 (t,J=7.8 Hz, 1H). MS m/z (M+H) 282.0

Example 88: Synthesis of2-fluoro-3-{2-[2-(hydroxymethyl)phenyl]ethynyl}benzoic acid

2-fluoro-3-{2-[2-(hydroxymethyl)phenyl]ethynyl}benzoic acid was preparedby the same procedure as example 86. ¹H NMR (300 MHz, CDCl₃) δ7.94-7.85(m, 1H), 7.71-7.61 (m, 1H), 7.58-7.47 (m, 2H), 7.43-7.34 (m, 1H),7.32-7.25 (m, 1H), 7.23-7.14 (m, 1H), 4.89 (d, J=20.9 Hz, 2H). MS m/z(M+) 270.7

Example 89: Synthesis of 2-fluoro-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoicacid

2-fluoro-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by thesame procedure as example 86. ¹H NMR (300 MHz, DMSO) δ 13.49 (s, 1H),9.20 (d, J=1.9 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 8.05-7.52 (m, 2H), 7.36(t, J=7.8 Hz, 1H). MS m/z (M+H) 248.0

Example 90: Synthesis of 3-[2-(pyridin-2-yl)ethynyl]benzoic acid

3-[2-(pyridin-2-yl)ethynyl]benzoic acid was prepared by the sameprocedure as example 78 starting with 3-bromo-benzoic acid methyl ester.¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H), 8.29 (s, 1H), 8.04 (d, J=7.9 Hz,1H), 7.78 (d, J=7.4 Hz, 1H), 7.71 (dd, J=7.7, 6.0 Hz, 1H), 7.55 (d,J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.28 (d, J=10.1 Hz, 1H). MS m/z(M+H) 224.0

Example 91: Synthesis of 3-[2-(pyridin-3-yl)ethynyl]benzoic acid

3-[2-(pyridin-3-yl)ethynyl]benzoic acid was prepared by the sameprocedure as example 90. ¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, 1H), 8.57(d, J=3.3 Hz, 1H), 8.23 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.31 (dd,J=7.4, 4.6 Hz, 2H). MS m/z (M+H) 224.1

Example 92: Synthesis of 3-(2-phenylethynyl)benzoic acid

3-(2-phenylethynyl)benzoic acid was prepared by the same procedure asexample 90. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (s, 1H), 8.00 (d, J=8.2 Hz,1H), 7.69 (s, 2H), 7.54 (d, J=3.5 Hz, 2H), 7.45 (d, J=7.7 Hz, 1H), 7.35(d, J=2.6 Hz, 2H). MS m/z (M+H) 223.1

Example 93: Synthesis of 3-[2-(pyridin-4-yl)ethynyl]benzoic acid

3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by the sameprocedure as example 90. ¹H NMR (300 MHz, CDCl₃) δ 8.63 (d, J=5.2 Hz,1H), 8.24 (s, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.47(t, J=8.0 Hz, 1H), 7.45-7.34 (m, 2H), 7.26 (m, 1H). MS m/z (M+H) 224.0

Example 94: Synthesis of 3-[2-(4-methoxyphenyl)ethynyl]benzoic acid

3-[2-(4-methoxyphenyl)ethynyl]benzoic acid was prepared by the sameprocedure as example 90. ¹H NMR (300 MHz, CDCl₃) δ 8.19 (s, 1H), 7.97(d, J=7.8 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.42(t, J=7.7 Hz, 1H), 6.89 (d, J=8.9 Hz, 2H). MS m/z (M+H) 253.0

Example 95: Synthesis of2-{4-[(dimethylamino)methyl]phenyl}-3-(2-phenylethynyl)benzoic acidtrifluoroacetic acid salt

2-Amino-3-phenylethynyl-benzoic acid methyl ester: To a sealed flask wasloaded a mixture of 2-amino-3-bromo-benzoic acid methyl ester (4 g, 17.4mmol), Pd(PPh₃)₂Cl₂ (618 mg, 0.88 mmol) and copper iodide (335 mg, 1.76mmol) in triethyl amine (80 mL). The mixture was degassed with N₂ for 10minutes, phenylacetylene (7.2 g, 70.5 mmol) was added and the mixturewas degassed with N₂ for 5 minutes. The reaction mixture was heated at90° C. for 17 hours. After cooling to ambient temperature, the crudemixture was filtered through celite and washed with dichloromethane. Thefiltrate was concentrated and purified by column chromatography througha silica gel cartridge (80 g) eluting with ethyl acetate/hexane (0-30%)to give 4.3 g (98%) of the product as a white solid.

2-Iodo-3-phenylethynyl-benzoic acid methyl ester: A solution of2-amino-3-phenylethynyl-benzoic acid methyl ester (1 g, 3.98 mmol) in1,4-dioxane was treated with concentrated hydrochloric acid (7.8 mL)slowly and stirred for 10 minutes. At 0° C. sodium nitrite (304 mg, 4.4mmol) in water (5 mL) was added and the reaction mixture was stirred at0° C. for 1 hour. Potassium iodide (6.8 g, 4.1 mmol) in water (5.5 mL)was added at 0° C. and the solution was stirred at room temperature for17 hours. Saturated sodium bicarbonate was added until bubbling ceasedand the solution was extracted with dichloromethane (15 mL×3), theorganic extracts were combined, dried (anhydrous sodium sulfate),concentrated and purified by column chromatography through a silica gelcartridge (40 g) eluting with ethyl acetate/hexane (0-20%) to give theproduct as a white solid (340 mg, 30%).

2-{4-[(dimethylamino)methyl]phenyl}-3-(2-phenylethynyl)benzoic acidtrifluoroacetic acid salt. A mixture of 2-iodo-3-phenylethynyl-benzoicacid methyl ester (25 mg, 0.069 mmol),dimethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amine(26 mg, 0.1 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (6.1 mg,0.007 mmol) and potassium carbonate (23 mg, 0.17 mmol) in 1,4-dioxane(0.8 mL) and water (0.2 mL) was degassed with N₂ for 10 minutes andheated at 90° C. for 17 hours. After cooling down the reaction mixturewas partitioned between water and ethyl acetate, the organic layer wasdried (sodium sulfate), filtered, concentrated and purified throughpreparative thin layer chromatography to give a solid intermediate. Tothis solid intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) wasadded sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and thesolution was stirred at room temperature for 18 hours. 1 N hydrochloricacid aqueous solution was added dropwise until pH=1 and the reactionmixture was purified through preparative HPLC to give 13 mg (42% for 2steps) of the pure product as a white solid. ¹H NMR (300 MHz, CDCl₃)δ=7.97 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.57-7.38 (m, 3H),7.37-7.09 (m, 7H), 4.03 (s, 2H), 2.67 (s, 6H). LCMS (ESI) m/z 356.1(M+1)⁺.

Example 96: Synthesis of3-(2-phenylethynyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acidtrifluoroacetic acid salt

3-(2-phenylethynyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acidtrifluoroacetic acid salt was prepared by the same procedure as example95. LCMS (ESI) m/z 304.1 (M+1)⁺.

Example 97: 3-(2-phenylethynyl)-2-(pyridin-4-yl)benzoic acidtrifluoroacetic acid salt

3-(2-phenylethynyl)-2-(pyridin-4-yl)benzoic acid trifluoroacetic acidsalt was prepared by the same procedure as example 95. ¹H NMR (300 MHz,CDCl₃) δ=8.74 (d, J=6.7 Hz, 2H), 8.19 (dd, J=1.2, 7.9 Hz, 1H), 7.85 (dd,J=1.3, 7.8 Hz, 1H), 7.77 (d, J=6.5 Hz, 2H), 7.61 (t, J=7.9 Hz, 1H),7.31-7.23 (m, 3H), 7.09 (dd, J=1.6, 8.1 Hz, 2H). LCMS (ESI) m/z 300.1(M+1)⁺.

Example 98: Synthesis of2-(4-methanesulfonylphenyl)-3-(2-phenylethynyl)benzoic acid

2-(4-methanesulfonylphenyl)-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 95. ¹H NMR (300 MHz, CDCl₃) δ=8.04-7.99(m, 3H), 7.82 (dd, J=1.2, 7.6 Hz, 1H), 7.58-7.48 (m, 3H), 7.29-7.22 (m,3H), 7.09-7.04 (m, 2H), 3.11 (s, 3H). LCMS (ESI) m/z 377.0 (M+1)⁺.

Example 99: Synthesis of 3-(2-phenylethynyl)-2-(1H-pyrazol-4-yl)benzoicacid

3-Phenylethynyl-2-(1H-pyrazol-4-yl)-benzoic acid was prepared by thesame procedure as example 95. ¹H NMR (300 MHz, CDCl₃) δ=8.03 (s, 2H),7.91 (d, J=8.0 Hz, 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.48 (t, J=7.8 Hz,1H), 7.35-7.27 (m, 5H). LCMS (ESI) m/z 289.1 (M+1)⁺.

Example 100: Synthesis of 3-(2-phenylethynyl)-2-(pyrimidin-5-yl)benzoicacid

3-(2-phenylethynyl)-2-(pyrimidin-5-yl)benzoic acid was prepared by thesame procedure as example 95. ¹H NMR (300 MHz, CDCl₃) δ=9.18 (s, 1H),8.74 (s, 2H), 8.06 (dd, J=1.5, 7.9 Hz, 1H), 7.81 (dd, J=1.3, 7.8 Hz,1H), 7.51 (t, J=7.8 Hz, 1H), 7.28-7.15 (m, 5H). LCMS (ESI) m/z 301.1(M+1)⁺.

Example 101: Synthesis of2-(1-methyl-1H-pyrazol-4-yl)-3-(2-phenylethynyl)benzoic acid

2-(1-methyl-1H-pyrazol-4-yl)-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 95. ¹H NMR (300 MHz, CDCl₃)δ=8.87 (br. s., 1H), 7.93-7.89 (m, 1H), 7.89 (s, 1H), 7.80 (dd, J=1.3,7.8 Hz, 1H), 7.70 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.36-7.26 (m, 5H),4.08 (s, 3H). LCMS (ESI) m/z 303.0 (M+1)⁺.

Example 102: Synthesis of3-(2-phenylethynyl)-2-(2-phenylpyrrolidin-1-yl)benzoic acid

A solution of methyl 2-fluoro-3-bromobenzoate (6.41 mmol) andphenylacetylene (7.76 mmol) in terahydrofuran/triethylamine (32 mL/32mL) was degassed using a N₂ gas balloon for 15 minutes in a sealed roundbottom flask. To this solution was addedBis(triphenylphosphine)palladium(II) dichloride (450 mg, 0.64 mmol) andcopper iodide (60 mg), sealed and heated to 80° C. for 16 hours. Thereaction mixture was then cooled to ambient temperature, filteredthrough celite using ethyl acetate (50 mL). The filtrate was thenconcentrated under reduced pressure and purified through silica gelcartridge eluting with ethyl acetate/hexanes to give the product as abrown liquid in 70% yield. To a stirring solution of2-fluoro-3-phenylethynyl-benzoic acid methyl ester (60 mg, 0.236 mmol)in dimethyl sulfoxide (2 mL) was added 2-phenylpyrrolidine (0.27 mmol),potassium carbonate (0.1 g, 0.7 mmol), and catalytic tetra butylammonium iodide. This solution was heated to 140° C. for 24 hours. Thereaction mixture was then cooled to ambient temperature diluted withethyl acetate (10 mL) washed with water (2×4 mL). The organic layerswere washed with 1N hydrochloric acid (2 mL), water (2 mL), brine (2 mL)dried (sodium sulfate), filtered and concentrated under reducedpressure. The resulting crude product was then dissolved interahydrofuran/methanol (1/1 mL) and added 2N sodium hydroxide solution(0.3 mL) and stirred for 24 hours at ambient temperature. This solutionwas then concentrated and neutralized to pH 4 using 1 N hydrochloricacid solution. The aqueous layer was then extracted using ethyl acetate(2×5 mL) and washed with water (2 mL) and brine (3 mL). The organiclayers were combined, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The resulting crude product was then purifiedusing reversed phase HPLC. ¹H NMR (300 MHz, CDCl₃) δ 8.14 (d, J=7.7 Hz,1H), 7.76 (d, J=7.7 Hz, 1H), 7.59 (dd, J=6.6, 3.1 Hz, 2H), 7.46 (q,J=3.7 Hz, 3H), 7.35 (t, J=7.7 Hz, 1H), 7.23 (bs, 5H), 5.52 (t, J=7.8 Hz,1H), 4.05-3.86 (m, 1H), 3.75 (s, 1H), 2.61-2.28 (m, 4H). MS m/z (M+H)368.1

Example 103: Synthesis of2-(3-(dimethylamino)pyrrolidin-1-yl)-3-(phenylethynyl)benzoic acid

2-(3-(dimethylamino)pyrrolidin-1-yl)-3-(phenylethynyl)benzoic acid wasprepared by the same procedure as example 102. ¹H NMR (300 MHz, CDCl₃) δ8.32 (dd, J=7.9, 1.7 Hz, 1H), 7.81 (dd, J=7.7, 1.7 Hz, 1H), 7.59-7.52(m, 2H), 7.51-7.41 (m, 4H), 3.82-3.80 (m, 1H), 3.11-2.90 (m, 2H), 2.82(s, 6H), 2.76-2.45 (m, 2H), 1.75-1.55 (m, 1H), 1.39 (dq, J=14.7, 7.3 Hz,1H). MS m/z (M+H) 335.2

Example 104: Synthesis of1-(2-carboxy-6-(phenylethynyl)phenyl)pyrrolidine-3-carboxylic acid

1-(2-carboxy-6-(phenylethynyl)phenyl)pyrrolidine-3-carboxylic acid wasprepared by the same procedure as example 102. ¹H NMR (300 MHz, CDCl₃) δ8.31 (d, J=6.9 Hz, 1H), 7.80-7.70 (m, 1H), 7.74 (ddd, J=8.5, 7.9, 4.7Hz, 1H), 7.53 (dd, J=6.7, 3.1 Hz, 1H), 7.48-7.33 (m, 3H), 7.09 (td,J=7.9, 0.9 Hz, 1H), 3.91 (m, 1H) 3.73 (bs, 1H), 3.21-2.91 (m, 2H), 2.53(m, 1H), 1.63 (bs, 1H), 1.40 (dd, J=14.7, 7.1 Hz, 1H). MS m/z (M+H)336.4

Example 105: Synthesis of(S)-2-(3-hydroxypyrrolidin-1-yl)-3-(phenylethynyl)benzoic acid

(S)-2-(3-hydroxypyaolidin-1-yl)-3-(phenylethynyl)benzoic acid wasprepared by the same procedure as example 102. ¹H NMR (300 MHz, CDCl₃) δ8.32 (d, J=7.9 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.50 (dd, J=13.1, 9.4Hz, 2H), 7.45-7.35 (m, 4H), 4.82 (s, 1H), 3.92 (d, J=12.1 Hz, 1H),3.87-3.69 (m, 3H), 3.49 (d, J=9.1 Hz, 1H), 2.46 (s, 1H), 2.25 (s, 1H).MS m/z (M+H) 308.2

Example 106: Synthesis of 3-(phenylethynyl)-2-(pyrrolidin-1-yl)benzoicacid

3-(phenylethynyl)-2-(pyrrolidin-1-yl)benzoic acid was prepared by thesame procedure as example 102. ¹H NMR (300 MHz, CD₃OD) δ 8.25 (dd,J=7.9, 1.6 Hz, 1H), 7.88 (dd, J=7.7, 1.5 Hz, 1H), 7.68-7.51 (m, 3H),7.47-7.33 (m, 3H), 3.85-3.75 (m, 4H), 2.49-2.19 (m, 4H). MS m/z (M+H)292.1

Example 107: Synthesis of 3-(phenylethynyl)-2-(piperazin-1-yl)benzoicacid

3-(phenylethynyl)-2-(piperazin-1-yl)benzoic acid was prepared by thesame procedure as example 102. ¹H NMR (300 MHz, CD₃OD) δ 7.70 (dd,J=3.4, 1.6 Hz, 1H), 7.67 (dd, J=3.6, 1.6 Hz, 1H), 7.63-7.58 (m, 2H),7.45-7.40 (m, 3H), 7.27 (td, J=7.7, 3.3 Hz, 1H), 3.67-3.55 (m, 4H), 3.35(dd, J=8.8, 4.2 Hz, 4H). MS m/z (M+H) 307.2

Example 108: Synthesis of 2-(benzylamino)-3-(phenylethynyl)benzoic acid

2-(benzylamino)-3-(phenylethynyl)benzoic acid was prepared by the sameprocedure as example 102. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (d, J=7.3 Hz,1H), 7.83 (d, J=7.3 Hz, 1H), 7.64-7.28 (m, 9H), 7.31-7.17 (m, 2H), 4.12(s, 2H). MS m/z (M+H) 328.6

Example 109: Synthesis of2-(4-phenyl-1H-1,2,3-triazol-1-yl)-3-(2-phenylethynyl)benzoic acid

To a stirring solution of methyl 2-amino-3-bromobenzoate (0.23 g, 1mmol) in water/1,4-dioxane (3.5/0.5 mL) at 0° C. was added concentratedhydrochloric acid (0.2 mL, 2.4 mmol) dropwise followed by a solution ofsodium nitrite (0.07 g, 1 mmol) in water (1 mL) dropwise. This solutionwas stirred for 1 hour at 0° C. after which a solution of sodium azide(0.07 g, 1 mmol) in water (1 mL) was added. The resultant mixture wasallowed to warm to ambient temperature and stirred for 3 hours. After 3hours, the reaction mixture was extracted with dichloromethane (2×10mL). The organic layers were combined, dried (sodium sulfate), filteredand concentrated under reduced pressure. The resulting crude product wasused as is in the next reaction. To a stirring solution of methyl2-azido-3-bromobenzoate (0.07 g, 0.27 mmol) in tert-butanol:water (1:1mL) was added alkyne (0.27 mmol), 1M sodium ascorbate solution in water(0.1 mL) and copper sulfate (˜5 mg). This solution was stirred for 24hours at ambient temperature. After 24 hours the reaction mixture wasextracted with ethyl acetate (2×10 mL). The organic layers were washedwith water (5 mL), brine (5 mL) and dried (sodium sulfate), filtered andconcentrated under reduced pressure. The resulting crude product waspurified through silica gel cartridge eluting with ethyl acetate/hexanesto give the product as a pale yellow solid in 45% overall yield.

A solution of 3-bromo-2-(4-phenyl-[1,2,3]triazol-1-yl)-benzoic acidmethyl ester (0.11 mmol) and phenylacetylene (0.11 mmol) interahydrofuran:triethylamine (1:1 mL) was deaerated using a N₂ gasballoon for 2 minutes. To this solution was addedBis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.011 mmol) andcopper iodide (5 mg) and heated to 80° C. for 16 hours. The reactionmixture was then cooled to ambient temperature, filtered through celiteusing ethyl acetate (5 mL). The resultant solution was the concentratedunder reduced pressure and purified via either short silica gelcartridge or preparative thin layer chromatography eluting with ethylacetate/hexanes. This product was then dissolved interahydrofuran/methanol (1/1 mL) and 2N sodium hydroxide solution (0.3mL) was added and the solution was stirred for 24 hours at ambienttemperature. This solution was then concentrated and neutralized to pH 4using 1 N hydrochloric acid solution. The aqueous layer was thenextracted using ethyl acetate (2×5 mL) and washed with brine (3 mL). Theorganic layers were combined, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The resulting crude product wasthen purified using reversed phase HPLC. ¹H NMR (300 MHz, CD₃OD) δ 8.74(s, 1H), 8.10 (dd, J=7.8, 1.5 Hz, 1H), 7.93 (dtd, J=5.0, 3.0, 1.8 Hz,3H), 7.74 (t, J=7.8 Hz, 1H), 7.53-7.42 (m, 2H), 7.41-7.32 (m, 1H), 7.27(tdd, J=10.1, 3.7, 1.9 Hz, 1H), 7.22-7.17 (m, 4H). MS m/z (M+H) 366.0.

Example 110: Synthesis of2-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl)benzoicacid

2-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl)benzoicacid was prepared by the same procedure as example 102. ¹H NMR (300 MHz,CD₃OD) δ 8.75 (s, 1H), 8.10 (dd, J=7.8, 1.5 Hz, 1H), 7.94 (dd, J=7.8,1.5 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.49 (dt, J=2.5, 1.5 Hz, 2H), 7.37(dd, J=8.2, 7.6 Hz, 1H), 7.28 (tdd, J=5.0, 4.5, 3.1 Hz, 1H), 7.23-7.18(m, 4H), 6.95 (ddd, J=8.2, 2.5, 1.1 Hz, 1H), 3.82 (d, J=20.1 Hz, 3H). MSm/z (M+H) 396.1

Example 111: Synthesis of3-(phenylethynyl)-2-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)benzoic acid

3-(phenylethynyl)-2-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)benzoic acidwas prepared by the same procedure as example 102. ¹H NMR (300 MHz,CD₃OD) δ 9.37 (d, J=1.9 Hz, 1H), 9.07 (s, 1H), 9.00-8.88 (m, 1H), 8.76(d, J=4.3 Hz, 1H), 8.16 (dd, J=7.9, 1.5 Hz, 1H), 8.06-8.01 (m, 1H), 7.99(dd, J=7.9, 1.5 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.34-7.26 (m, 1H),7.26-7.17 (m, 4H). MS m/z (M+H) 367.1

Example 112: Synthesis of2-(4-(3-hydroxypropyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl)benzoicacid

2-(4-(3-hydroxypropyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl)benzoicacid was prepared by the same procedure as example 102. ¹H NMR (300 MHz,CD₃OD) δ 8.09 (s, 1H), 8.08-8.01 (m, 1H), 7.90 (dd, J=7.8, 1.5 Hz, 1H),7.70 (t, J=7.8 Hz, 1H), 7.39-7.21 (m, 5H), 3.60 (t, J=6.4 Hz, 2H), 2.92(dd, J=17.8, 10.3 Hz, 2H), 1.94 (dq, J=9.8, 6.4 Hz, 2H). MS m/z (M+H)348.1

Example 113: Synthesis ofN-(Dimethylsulfamoyl)-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamide

To a solution of 3-phenylethynyl-2-pyrrol-1-yl-benzoic acid (50 mg, 0.17mmol) in N,N-dimethylformamide (0.25 mL) was added N,N-dimethylsulfamide(43 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (67 mg, 0.35 mmol), and hydroxyl-benzotriazole hydrate (43mg, 0.35 mmol). After 16 hours, the reaction mixture was diluted withethyl acetate (40 mL) and washed with dilute hydrochloric acid (30 mL,0.1N), saturated aqueous sodium hydrogen carbonate (30 mL) and saturatedaqueous sodium chloride (25 mL). The organic layer was concentrated atreduce pressure. The resulting oil was purified by column chromatographythrough a silica gel cartridge (4 g) eluting with ethyl acetate/hexane(1/4 to 1/2) to give the product as a white foam. ¹H NMR (300 MHz,CDCl₃) δ=7.95 (dd, J=1.6, 7.8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.54 (t,J=7.8 Hz, 1H), 7.36-7.23 (m, 5H), 6.92 (t, J=2.2 Hz, 2H), 6.54 (t, J=2.2Hz, 2H), 2.90 (s, 6H). MS (ES⁺)=394 (MH)⁺.

Example 114: Synthesis ofN-(Dimethylsulfamoyl)-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzamide

N-(Dimethylsulfamoyl)-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)was prepared by the same procedure as example 113. ¹H NMR (300 MHz,CDCl₃) δ=7.95 (dd, J=1.6, 7.8 Hz, 1H), 7.77 (dd, J=1.5, 7.6 Hz, 1H),7.54 (t, J=7.8 Hz, 1H), 7.39 (br s, 1H), 7.31-7.20 (m, 1H), 7.02-6.90(m, 1H), 6.91 (t, J=2.2 Hz, 2H), 6.54 (t, J=2.2 Hz, 2H), 2.90 (s, 6H).MS (ES⁺)=412 (MH)⁺.

Example 115: Synthesis ofN-(morpholine-4-sulfonyl)-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamide

N-(morpholine-4-sulfonyl)-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamidewas prepared by the same procedure as example 113. ¹H NMR (300 MHz,CDCl₃) δ 7.92 (dt, J=15.9, 8.0 Hz, 1H), 7.87-7.74 (m, 1H), 7.54 (t,J=7.8 Hz, 1H), 7.46 (bs, 1H), 7.36-7.22 (m, 5H), 7.00-6.85 (m, 2H),6.59-6.48 (m, 2H), 3.70 (m, 4H), 3.49-3.05 (m, 4H). MS m/z (M+H) 436.4.

Example 116: Synthesis ofN-[(1,1-dioxo-4-thiomorpholin-4-yl)sulfonyl]-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamide

N-[(1,1-dioxo-4-thiomorpholin-4-yl)sulfonyl]-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamidewas prepared by the same procedure as example 113. ¹H NMR (300 MHz,CDCl₃) δ 7.94 (dd, J=7.9, 1.6 Hz, 1H), 7.83 (dd, J=7.8, 1.6 Hz, 1H),7.57 (t, J=7.8 Hz, 1H), 7.52 (bs, 1H), 7.36-7.22 (m, 5H), 7.00-6.85 (m,2H), 6.56 (t, J=2.1 Hz, 2H), 3.96-3.79 (m, 4H), 3.25-2.96 (m, 4H). MSm/z (M+H) 484.7

Example 117: Synthesis of3-[2-(4-fluorophenyl)ethynyl]-N-methanesulfonyl-2-(1H-pyrrol-1-yl)benzamide

3-[2-(4-fluorophenyl)ethynyl]-N-methanesulfonyl-2-(1H-pyrrol-1-yl)benzamidewas prepared by the same procedure as example 113. ¹H NMR (300 MHz,CD₃OD) δ 7.64 (dd, J=7.6, 1.6 Hz, 1H), 7.54 (dd, J=7.7, 1.6 Hz, 1H),7.43 (t, J=7.7 Hz, 1H), 7.36-7.26 (m, 2H), 7.10-7.00 (m, 2H), 6.96-6.89(m, 2H), 6.29-6.22 (m, 2H), 2.86 (s, 3H). MS m/z (M+H) 383.0

Example 118: Synthesis of3-(phenylethynyl)-2-(1H-pyrrol-1-yl)-N-sulfamoylbenzamide

3-(phenylethynyl)-2-(1H-pyrrol-1-yl)-N-sulfamoyl benzamide was preparedby the same procedure as example 113. ¹H NMR (300 MHz, CDCl₃) δ 7.91(dd, J=7.8, 1.6 Hz, 1H), 7.82 (dd, J=7.8, 1.6 Hz, 1H), 7.60-7.52 (m,1H), 7.50 (bs, 1H), 7.37-7.26 (m, 5H), 6.97-6.91 (m, 2H), 6.60-6.52 (m,3H), 5.12 (bs, 2H). MS m/z (M+H) 366.3

Example 119: Synthesis of 2-(4-methoxyphenyl)-3-(2-phenylethynyl)benzoicacid

To a stirring solution of 2-bromo-3-iodobenzoic acid (1 g, 3.1 mmol) indimethyl sulfoxide (5 mL) was added potassium carbonate (2.1 g, 15 mmol)followed by iodomethane (0.7 g, 4.6 mmol) and stirred for 12 hours atambient temperature. The reaction mixture was then diluted with ethylacetate (40 mL) washed with water (2×10 mL). The organic layer werewashed brine (10 mL) dried (sodium sulfate), filtered and concentratedunder reduced pressure. The resultant crude product was purified throughsilica gel cartridge eluting with ethyl acetate/hexanes to give methyl2-bromo-3-iodobenzoate as a pale yellow liquid in 90% overall yield.

A solution of methyl 2-bromo-3-iodobenzoate (1 g, 2.9 mmol) andphenylacetylene (4.4 mmol) in terahydrofuran:triethylamine (20:20 mL)was deaerated using a N₂ gas balloon for 15 minutes in a round bottomflask. To this solution was added Bis(triphenylphosphine)palladium(II)dichloride (210 mg, 0.3 mmol) and copper iodide (30 mg) and stirred for16 hours at ambient temperature. The reaction mixture was then filteredthrough celite using ethyl acetate (50 mL). The resultant solution wasthe concentrated under reduced pressure and purified through silica gelcartridge eluting with ethyl acetate/hexanes to give the product as abrown solid. To a stirring solution of this product (0.05 g, 0.16 mmol)in 1,4-dioxane/water (1/1 mL) was added 4-methoxyphenylboronic acid(0.32 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (15 mg, 0.02 mmol)and potassium carbonate (45 mg, 0.32 mmol) and heated to 80° C. for 16hours. The resultant mixture was allowed to cool to ambient temperatureand was diluted with ethyl acetate (5 mL). The aqueous layer wasextracted with ethyl acetate (2×2 mL) and the combined organic layerswere washed with water (2 mL), brine (2 mL), dried (sodium sulfate),filtered and concentrated under reduced pressure. The resultant crudeproduct was purified either through a small silica gel cartridge orpreparative thin layer chromatography eluting with ethylacetate/hexanes. The product so obtained was then dissolved interahydrofuran/methanol (1/1 mL) and added 2N sodium hydroxide solution(0.3 mL) and stirred for 24 hours at ambient temperature. This solutionwas then concentrated and neutralized to pH 4 using 1 N hydrochloricacid solution. The aqueous layer was then extracted using ethyl acetate(2×5 mL) and washed with water (2 mL) and brine (3 mL). The organiclayers were combined, dried (sodium sulfate), filtered and concentratedunder reduced pressure. The resulting crude product was then purifiedusing reversed phase HPLC. ¹H NMR (300 MHz, CDCl₃) δ 7.74 (dd, J=7.7,5.2 Hz, 2H), 7.38 (dd, J=9.7, 5.8 Hz, 1H), 7.33 (dt, J=5.0, 2.8 Hz, 1H),7.24 (m, 6H), 7.05-6.82 (m, 2H), 3.62 (s, 3H). MS m/z (M−H₂O) 312.0

Example 120: Synthesis of 2-(3-methoxyphenyl)-3-(2-phenylethynyl)benzoicacid

2-(3-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.75 (dd,J=9.3, 7.8 Hz, 2H), 7.39 (dd, J=12.3, 4.4 Hz, 1H), 7.36-7.29 (m, 1H),7.28-7.22 (m, 3H), 7.22-7.15 (m, 2H), 6.99-6.90 (m, 3H), 3.61 (s, 3H).MS m/z (M−H₂O) 312.1

Example 121: Synthesis of 2-(2-methoxyphenyl)-3-(2-phenylethynyl)benzoicacid

2-(2-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.94-7.81 (m,1H), 7.81-7.67 (m, 1H), 7.47-7.32 (m, 2H), 7.28 (dt, J=5.5, 2.7 Hz, 1H),7.25-7.15 (m, 3H), 7.16-7.10 (m, 2H), 7.05 (td, J=7.4, 1.0 Hz, 1H), 6.96(dt, J=7.9, 4.0 Hz, 1H), 3.64 (s, 3H). MS m/z (M−H₂O) 312.1

Example 122: Synthesis of 3-(2-phenylethynyl)-2-(quinolin-3-yl)benzoicacid

3-(2-phenylethynyl)-2-(quinolin-3-yl)benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 8.92 (bs, 1H),8.24-8.15 (m, 2H), 7.97 (dd, J=7.8, 1.3 Hz, 1H), 7.91-7.81 (m, 2H), 7.77(t, J=7.7 Hz, 1H), 7.59 (t, J=6.9 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H),7.24-7.06 (m, 3H), 7.06-6.98 (m, 2H). MS m/z (M+H) 350.1

Example 123: Synthesis of 2-cyclopropyl-3-(2-phenylethynyl)benzoic acid

2-cyclopropyl-3-(2-phenylethynyl)benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.67-7.44 (m, 4H),7.44-7.31 (m, 3H), 7.30-7.15 (m, 1H), 2.34-2.10 (m, 1H), 1.15-0.84 (m,2H), 0.79-0.50 (m, 2H). MS m/z (M+H) 263.1

Example 124: Synthesis of 2-phenyl-3-(2-phenylethynyl)benzoic acid

2-phenyl-3-(2-phenylethynyl)benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.86-7.76 (m, 1H),7.77-7.66 (m, 1H), 7.52-7.27 (m, 6H), 7.30-7.18 (m, 3H), 7.18-7.02 (m,2H). MS m/z (M+Na) 321.0.

Example 125: Synthesis of 2-(4-methylphenyl)-3-(2-phenylethynyl)benzoicacid

2-(4-methylphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.75 (ddd,J=10.5, 7.8, 1.4 Hz, 2H), 7.51-7.30 (m, 1H), 7.33-7.25 (m, 6H),7.20-7.15 (m, 3H), 2.43 (s, 3H). MS m/z (M+Na) 335.1.

Example 126: Synthesis of2-(6-methoxypyridin-3-yl)-3-(2-phenylethynyl)benzoic acid

2-(6-methoxypyridin-3-yl)-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 8.13(dd, J=2.5, 0.7 Hz, 1H), 7.84 (dd, J=7.8, 1.4 Hz, 1H), 7.79-7.73 (m,1H), 7.65 (dd, J=8.5, 2.5 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.32-7.20 (m,5H), 6.83 (ddd, J=8.6, 2.0, 0.7 Hz, 1H), 3.68 (s, 3H). MS m/z (M+H)330.0

Example 127: Synthesis of2-[6-(dimethylamino)pyridin-3-yl]-3-(2-phenylethynyl)benzoic acid

2-[6-(dimethylamino)pyridin-3-yl]-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ8.17 (dd, J=2.5, 0.7 Hz, 1H), 7.75 (ddd, J=9.2, 7.8, 1.4 Hz, 2H),7.60-7.53 (m, 1H), 7.41-7.32 (m, 1H), 7.32-7.21 (m, 5H), 6.58 (dd,J=8.8, 0.7 Hz, 1H), 3.13 (s, 6H). MS m/z (M+H) 343.1

Example 128: Synthesis of2-[3-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid

2-[3-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.85(dd, J=7.8, 1.4 Hz, 1H), 7.75 (dd, J=7.8, 1.4 Hz, 1H), 7.48-7.33 (m,5H), 7.25 (dd, J=5.0, 2.0 Hz, 3H), 7.15 (dd, J=6.5, 3.3 Hz, 2H), 4.67(s, 2H). MS m/z (M+H) 329.0.

Example 129: Synthesis of 2-(1H-indol-6-yl)-3-(2-phenylethynyl)benzoicacid

2-(1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, DMSO) δ 11.18 (s, 1H),7.74 (dd, J=7.7, 1.3 Hz, 1H), 7.70-7.63 (m, 1H), 7.57 (d, J=8.1 Hz, 1H),7.45 (t, J=7.7 Hz, 1H), 7.39 (dd, J=7.2, 4.7 Hz, 2H), 7.27 (dd, J=9.4,3.2 Hz, 3H), 7.12 (dd, J=7.6, 1.9 Hz, 2H), 7.02 (dd, J=8.1, 1.5 Hz, 1H),6.46 (s, 1H). MS m/z (M+H) 338.0

Example 130: Synthesis of2-[4-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid

2-[4-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ7.83-7.77 (m, 1H), 7.74 (dd, J=7.8, 0.7 Hz, 1H), 7.42 (t, J=7.4 Hz, 1H),7.39-7.33 (m, 5H), 7.28-7.19 (m, 3H), 7.19-7.09 (m, 2H), 4.77 (s, 2H).MS m/z (M+H) 329.0

Example 131: Synthesis of2-(1-benzofuran-5-yl)-3-(2-phenylethynyl)benzoic acid

2-(1-benzofuran-5-yl)-3-(2-phenylethynyl)benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 7.81-7.76(m, 2H), 7.74 (dd, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.55 (d,J=8.5 Hz, 1H), 7.46 (dd, J=9.8, 5.8 Hz, 1H), 7.34-7.26 (m, 1H),7.25-7.13 (m, 3H), 7.07-6.96 (m, 2H), 6.88 (dd, J=2.2, 0.9 Hz, 1H). MSm/z (M+H) 339.0

Example 132: Synthesis of2-(1-benzothiophen-5-yl)-3-(2-phenylethynyl)benzoic acid

2-(1-benzothiophen-5-yl)-3-(2-phenylethynyl)benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 7.95 (d,J=8.3 Hz, 1H), 7.86-7.79 (m, 2H), 7.75 (dd, J=7.8, 1.3 Hz, 1H), 7.60 (d,J=5.5 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.41 (dd, J=5.5, 0.7 Hz, 1H),7.35 (dd, J=8.3, 1.6 Hz, 1H), 7.26-7.08 (m, 3H), 7.01-6.90 (m, 2H). MSm/z (M−H₂O) 337.0

Example 133: Synthesis of2-(1-methyl-1H-indol-5-yl)-3-(2-phenylethynyl)benzoic acid

2-(1-methyl-1H-indol-5-yl)-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 7.72(dd, J=3.9, 1.4 Hz, 1H), 7.70 (dd, J=4.1, 1.4 Hz, 1H), 7.60 (d, J=1.1Hz, 1H), 7.45-7.37 (m, 3H), 7.26-7.11 (m, 5H), 7.06 (dt, J=8.2, 2.1 Hz,2H), 3.85 (s, 3H). MS m/z (M+H) 352.0

Example 134: Synthesis of2-(3-methanesulfonamidophenyl)-3-(2-phenylethynyl)benzoic acid

2-(3-methanesulfonamidophenyl)-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.75 (dd, J=7.8, 1.3 Hz, 1H), 7.48 (t,J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.33-7.23 (m, 5H), 7.20-7.09 (m,3H), 2.83 (s, 3H). MS m/z (M−H₂O) 373.9

Example 135: Synthesis of 2-(naphthalen-2-yl)-3-(2-phenylethynyl)benzoicacid

2-(naphthalen-2-yl)-3-(2-phenylethynyl)benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 8.11-7.70 (m,6H), 7.68-7.39 (m, 4H), 7.22-7.01 (m, 3H), 7.00-6.85 (m, 2H). MS m/z(M+H) 349.1.

Example 136: Synthesis of2-(1-methyl-1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid

2-(1-methyl-1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.87(dd, J=7.8, 1.4 Hz, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.66 (dd, J=8.1,0.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.23-7.11 (m, 4H), 7.09 (d, J=3.1 Hz,1H), 7.05-6.99 (m, 2H), 6.53 (dd, J=3.1, 0.8 Hz, 1H), 3.74 (d, J=6.5 Hz,3H). MS m/z (M+H) 352.0

Example 137: Synthesis of2-{2-[(2-hydroxyethyl)sulfamoyl]phenyl}-3-(2-phenylethynyl)benzoic acid

2-{2-[(2-hydroxyethyl)sulfamoyl]phenyl}-3-(2-phenylethynyl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.91 (ddd, J=7.6, 5.6, 1.4 Hz, 2H), 7.85-7.75 (m, 2H), 7.64(td, J=7.6, 0.5 Hz, 1H), 7.60-7.56 (m, 1H), 7.53 (t, J=7.8 Hz, 1H),7.32-7.18 (m, 3H), 7.14 (ddd, J=4.3, 3.8, 2.5 Hz, 2H), 3.44 (t, J=5.9Hz, 2H), 2.89 (t, J=5.9 Hz, 2H). MS m/z (M+H) 422.2

Example 138: Synthesis of2-[4-(cyclopropylcarbamoyl)phenyl]-3-(2-phenylethynyl)benzoic acid

2-[4-(cyclopropylcarbamoyl)phenyl]-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.86 (ddd, J=5.7, 3.5, 1.6 Hz, 3H), 7.76 (dd, J=7.8, 1.3 Hz, 1H), 7.49(t, J=7.8 Hz, 1H), 7.45-7.39 (m, 2H), 7.32-7.16 (m, 3H), 7.16-7.02 (m,2H), 2.88 (ddd, J=11.1, 7.3, 3.9 Hz, 1H), 0.89-0.76 (m, 2H), 0.71-0.60(m, 2H). MS m/z (M+H) 382.4

Example 139: Synthesis of2-(1-methyl-1H-indazol-6-yl)-3-(2-phenylethynyl)benzoic acid

2-(1-methyl-1H-indazol-6-yl)-3-(2-phenylethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ8.04 (d, J=0.8 Hz, 1H), 7.84 (dt, J=7.8, 4.1 Hz, 1H), 7.77 (dd, J=7.9,1.3 Hz, 2H), 7.49-7.38 (m, 2H), 7.24-7.10 (m, 4H), 7.04-6.93 (m, 2H),3.56 (s, 3H). MS m/z (M+) 352.6

Example 140: Synthesis of3-((3-hydroxyphenyl)ethynyl)-2-(quinolin-3-yl)benzoic acid

To a stirring solution of 2-amino-3-bromobenzoic acid (1 g, 4.65 mmol)in water/1,4-dioxane (20 mL/2 mL) at 0° C. was added concentratedhydrochloric acid (1 mL, 11.2 mmol) dropwise followed by a solution ofsodium nitrite (0.32 g, 4.65 mmol) in 10 mL water dropwise. Thissolution was stirred for 1 hour at 0° C. after which a solution ofpotassium iodide (6.9 g, 42 mmol) in 12 mL water was added. Theresultant mixture was allowed to warm to ambient temperature and stirredfor 12 hours. After 12 hours the reaction mixture was extracted withethyl acetate (2×50 mL). The organic layers were combined, washed withsodium thiosulfate (2×10 mL), water (10 mL), brine (10 mL), dried(sodium sulfate), filtered and concentrated under reduced pressure. Thiscrude mixture was dissolved in dimethyl sulfoxide (5 mL) and potassiumcarbonate (2.1 g, 15 mmol) was added followed by iodomethane (0.8 g, 5.6mmol) and stirred for 12 hours at ambient temperature. The reactionmixture was then diluted with ethyl acetate (40 mL) washed with water(2×10 mL). The organic layer were washed brine (10 mL) dried (sodiumsulfate), filtered and concentrated under reduced pressure. Theresultant crude product was purified through silica gel cartridgeeluting with ethyl acetate/hexanes to give methyl 2-iodo-3-bromobenzoateas a pale yellow liquid in 85% overall yield.

To a stirring solution of methyl 2-iodo-3-bromobenzoate (1 g, 3.3 mmol)in 1,4-dioxane/water (10 mL/10 mL) was added quinolin-3-yl boronic acid(5 mmol), [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II),complex with dichloromethane (0.24 g, 0.33 mmol) and potassium carbonate(0.9 g, 6.6 mmol) and heated to 40° C. for 16 hours. The resultantmixture was allowed to cool to ambient temperature and was diluted withethyl acetate (50 mL). The aqueous layer was extracted with ethylacetate (2×20 mL) and the combined organic layers were washed with water(10 mL), brine (10 mL), dried (sodium sulfate), filtered andconcentrated under reduced pressure. The resultant crude product waspurified through silica gel cartridge eluting with ethyl acetate/hexanesto give the product. A solution of 3-bromo-2-quinolin-3-yl-benzoic acidmethyl ester (0.11 mmol) and 3-hydroxyphenylacetylene (0.11 mmol) inN,N-dimethylformamide/triethylamine (1 mL/1 mL) was degassed using a N₂gas balloon for 2 minutes. To this solution was addedBis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.011 mmol) andcopper iodide (5 mg) and heated to 100° C. for 16 hours. The reactionmixture was then cooled to ambient temperature, filtered through celiteusing ethyl acetate (10 mL). The resultant solution were washed with 1Nhydrochloric acid (2 mL), water (2×2 mL), brine (2 mL), dried (sodiumsulfate), filtered and concentrated under reduced pressure. Theresultant crude product was purified through either a short silica gelcartridge. The product so obtained was then dissolved interahydrofuran/methanol (1 mL/1 mL) and added 2N sodium hydroxidesolution (0.3 mL) and stirred for 24 hours at ambient temperature. Thissolution was then concentrated and neutralized to pH 4 using 1 Nhydrochloric acid solution. The aqueous layer was then extracted usingethyl acetate (2×5 mL) and washed with water (2 mL) and brine (3 mL).The organic layers were combined, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The resulting crude product wasthen purified using reversed phase HPLC. ¹H NMR (300 MHz, CD₃OD) δ9.20(d, J=1.8 Hz, 1H), 8.92 (s, 1H), 8.34-8.12 (m, 3H), 8.09 (t, J=7.8 Hz,1H), 8.02-7.82 (m, 3H), 7.68 (t, J=7.9 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H),6.68 (d, J=9.8 Hz, 1H), 6.48-6.27 (m, 2H). MS m/z (M+H) 366.0

Example 141: Synthesis of3-(5-hydroxypent-1-ynyl)-2-(quinolin-3-yl)benzoic acid

3-(5-hydroxypent-1-ynyl)-2-(quinolin-7-yl)benzoic acid was prepared bythe same procedure as example 140. ¹H NMR (300 MHz, CD₃OD) δ 9.23 (bs,1H), 8.97 (dd, J=4.8, 1.7 Hz, 1H), 8.29 (td, J=8.5, 3.7 Hz, 2H),8.22-8.09 (m, 2H), 7.95 (dt, J=7.4, 6.0 Hz, 1H), 7.83 (ddd, J=7.6, 6.1,1.3 Hz, 1H), 7.62 (td, J=7.9, 2.8 Hz, 1H), 4.14-3.56 (m, 2H), 3.20 (t,J=6.2 Hz, 1H), 2.29-2.19 (m, 2H), 1.61 (m, 1H), 1.45-1.08 (m, 1H). MSm/z (M+H) 332.1

Example 142: Synthesis of3-((4-methoxyphenyl)ethynyl)-2-(quinolin-3-yl)benzoic acid

3-((4-methoxyphenyl)ethynyl)-2-(quinolin-7-yl)benzoic acid was preparedby the same procedure as example 140. ¹H NMR (300 MHz, DMSO) δ 8.81 (d,J=2.2 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.05 (t, J=9.3 Hz, 2H), 7.92 (dd,J=7.8, 1.3 Hz, 1H), 7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.79 (ddd, J=8.4, 6.9,1.5 Hz, 1H), 7.67-7.56 (m, 2H), 7.01-6.87 (m, 2H), 6.85-6.60 (m, 2H),3.68 (s, 3H). MS m/z (M+H) 380.2

Example 143: Synthesis of3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-(quinolin-3-yl)benzoic acid

3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-(quinolin-3-yl)benzoic acid wasprepared by the same procedure as example 140. ¹H NMR (300 MHz, DMSO) δ9.04 (d, J=1.5 Hz, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H),8.20-8.08 (m, 1H), 8.08-7.97 (m, 3H), 7.91-7.82 (m, 1H), 7.77-7.67 (m,2H), 7.41 (d, J=4.5 Hz, 1H), 7.14 (dd, J=4.5, 1.5 Hz, 1H). MS m/z (M+)390.9

Example 144: Synthesis of3-[(1E)-3-methoxyprop-1-en-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[(1E)-3-methoxyprop-1-en-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid: Amixture of 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester (60 mg, 0.214mmol), 2-(3-methoxy-propenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(85 mg, 0.428 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (16 mg,0.0214 mmol) and potassium carbonate (59 mg, 0.428 mmol) in 1,4-dioxane(0.8 mL) and water (0.8 mL) was degassed with N₂ for 10 minutes andheated at 90° C. for 17 hours. After cooling down the reaction mixturewas partitioned between water and ethyl acetate, the organic layer wasdried (sodium sulfate), filtered, concentrated and purified throughpreparative thin layer chromatography to give a solid intermediate. Tothis solid intermediate in dimethylsulfoxide (0.5 mL) was added sodiumhydroxide solution (10% in water, 0.5 mL) and the solution was heated at100° C. for 24 hours. 1 N hydrochloric acid aqueous solution was addeddropwise until pH=1 and the reaction mixture was purified throughpreparative HPLC to give the product as a white solid. ¹H NMR (300 MHz,CDCl₃) δ=7.85-7.76 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 6.67 (t, J=2.2 Hz,2H), 6.36-6.17 (m, 3H), 6.04 (d, J=16.1 Hz, 1H), 3.97 (dd, J=1.3, 6.0Hz, 2H), 3.30 (s, 3H). LCMS (ESI) m/z 258.0 (M+1)⁺.

Example 145: Synthesis of3-[(E)-2-phenylethenyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[(E)-2-phenylethenyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared bythe same procedure as example 144. ¹H NMR (300 MHz, CDCl₃) δ=7.95 (dd,J=1.2, 8.2 Hz, 1H), 7.86 (dd, J=1.5, 7.6 Hz, 1H), 7.50 (t, J=7.8 Hz,1H), 7.34-7.23 (m, 5H), 7.05 (d, J=16.5 Hz, 1H), 6.76 (t, J=2.1 Hz, 2H),6.47 (d, J=16.4 Hz, 1H), 6.37 (t, J=2.2 Hz, 2H). LCMS (ESI) m/z 290.0(M+1)⁺.

Example 146: Synthesis of3-[(E)-2-(4-fluorophenyl)ethenyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[(E)-2-(4-fluorophenyl)ethenyl]-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 144. ¹H NMR (300 MHz, CDCl₃)δ=7.95-7.83 (m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.32-7.24 (m, 3H),7.04-6.94 (m, 2H), 6.75 (t, J=3.2 Hz, 2H), 6.40-6.33 (m, 3H). LCMS (ESI)m/z 308.0 (M+1)⁺.

Example 147: Synthesis of 3-(2-phenylethyl)-2-(1H-pyrrol-1-yl)benzoicacid

A solution of Example 146 (50 mg, 0.173 mmol) and 10% Pd—C (20 mg) inmethanol (3 mL) and chloroform (1 mL) was shaked under hydrogen at 40psi for 4 hours in Parr-Shaker. The solution was filtered through celiteand the filtrate was concentrated. The residue was purified throughpreparative HPLC to give the product as a white solid. ¹H NMR (300 MHz,CDCl₃) δ=7.80 (dd, J=1.7, 7.3 Hz, 1H), 7.49-7.37 (m, 2H), 7.25-7.12 (m,3H), 7.01-6.95 (m, 2H), 6.63 (t, J=2.2 Hz, 2H), 6.26 (t, J=2.1 Hz, 2H),2.75-2.60 (m, 4H). LC/MS (ESI) m/z 274.1 (M−H₂O)⁺.

Example 148: Synthesis of 3-(2-phenylethyl)-2-(pyrrolidin-1-yl)benzoicacid

3-(2-Phenylethyl)-2-(pyrrolidin-1-yl)benzoic acid was isolated asanother product in synthesizing Example 147. ¹H NMR (300 MHz, CDCl₃)δ=12.09 (br. s., 1H), 8.25 (dd, J=1.8, 7.6 Hz, 1H), 7.61 (dd, J=1.6, 7.8Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.12 (m, 3H), 7.16-7.12 (m, 2H),3.40-2.85 (m, 8H), 2.23-2.10 (m, 4H). LCMS (ESI) m/z 296.1 (M+H)⁺.

Example 149: Synthesis of3-[2-(4-fluorophenyl)ethyl]-2-(1H-pyrrol-1-yl)benzoic acid

3-[2-(4-fluorophenyl)ethyl]-2-(1H-pyrrol-1-yl)benzoic acid was preparedby the same procedure as example 147. LCMS (ESI) m/z 310.1 (M+H)⁺.

Example 150: Synthesis of2-(1H-1,3-benzodiazol-6-yl)-3-(2-phenylethynyl)benzoic acid

2-(1H-1,3-benzodiazol-6-yl)-3-(2-phenylethynyl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ 9.37 (s,1H), 7.89 (d, J=8.5 Hz, 1H), 7.85 (d, J=7.9 Hz, 2H), 7.80 (s, 1H), 7.58(dd, J=8.0, 7.5 Hz, 1H), 7.51 (dd, J=8.5, 1.5 Hz, 1H), 7.37-7.23 (m,3H), 7.14-7.04 (m, 2H). MS m/z (M+H) 339.0

Example 151: Synthesis of2-(quinolin-3-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(quinolin-3-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid wasprepared by the same procedure as example 140. ¹H NMR (300 MHz, DMSO) δ9.02 (d, J=1.9 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.52 (s, 1H), 8.11 (d,J=8.5 Hz, 2H), 8.02 (dd, J=7.8, 1.3 Hz, 1H), 7.97 (dd, J=7.8, 1.3 Hz,1H), 7.86 (t, J=7.1 Hz, 1H), 7.74-7.64 (m, 2H), 7.63 (d, J=1.9 Hz, 1H).MS m/z (M+) 356.9

Example 152: Synthesis of3-Phenylethynyl-2-pyrrol-1-yl-benzenesulfonamide

2-Amino-3-bromo-benzenesulfonamide: To a solution of chlorosulfonylisocyanate (3.78 g, 26.7 mmol) in nitroethane (20 mL) at 50° C. wasadded 2-bromoaniline (4.0 g, 23.3 mmol) in nitroethane (30 mL). After 5minutes aluminum chloride (4.0 g, 30.2 mmol) was added in three portionsand the mixture was heated to reflux at 110° C. for 30 minutes. Thereaction mixture was cooled to ambient temperature and poured onto ice(100 g) and the resulting suspension in water was stirred for 10minutes. The resulting slurry was filtered and rinsed with water (50 mL)and diethyl ether (50 mL) to give a gray green solid (2.77 g). Thissolid was added to sulfuric acid (50%, 30 mL) at 145° C. in threeportions allowing foaming to subside between additions. The mixture washeated for an additional 30 minutes and cooled to ambient temperature.The mixture was then poured over ice (100 g) and neutralized withaqueous sodium hydroxide (6N) to pH 7 to give a white slurry. Thismixture was extracted with isopropyl acetate (3×50 mL). The combinedorganic extracts were dried with sodium sulfate, filtered andconcentrated to a white solid. ¹H NMR (DMSO-d₆) δ 7.63-7.50 (m, 2H),7.48 (br s, 2H), 6.61 (J=7.9 Hz, 1H), 5.85 (br s, 2H). MS (ES⁺)=251(MH)⁺.

3-Bromo-2-pyrrol-1-yl-benzenesulfonamide: To a slurry of2,5-dimethoxytetrahydrofuran (950 mg, 7.2 mmol) and 4-chloropyridinehydrochloride (1.08 g, 7.2 mmol) in 1,4-dioxane (50 mL) was added2-amino-3-bromo-benzenesulfonamide (1.5 g, 6.0 mmol) and the mixture washeated to reflux for 2 hours. The reaction mixture was allowed to coolto ambient temperature and was poured into water (200 mL). The resultingslurry was vigorously stirred for 2 hours and filtered. The filtratedwas extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried with magnesium sulfate, filtered and concentrated atreduced pressure. The resulting oil was purified by columnchromatography through a silica gel cartridge (4 g) eluting with ethylacetate/hexane (1:9 to 1:2) to give the product as a white solid. ¹H NMR¹H NMR (300 MHz, DMSO) δ=8.02-7.98 (m, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.97(br s, 2H), 6.72 (t, J=2.1 Hz, 2H), 6.20 (t, J=2.1 Hz, 2H). MS (ES⁺)=301(MH)⁺.

3-Phenylethynyl-2-pyrrol-1-yl-benzenesulfonamide. To a degassed solutionof 3-bromo-2-pyrrol-1-yl-benzenesulfonamide (170 mg, 0.56 mmol) intriethylamine (1.7 mL), phenylacetylene (115 mg, 124 μL, 1.13 mmol) andcopper (I) iodide (5.4 mg, 0.028 mmol) in a sealed tube was addedbis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.056 mmol). Thetube was sealed and heated at 90° C. for 16 hours. The reaction mixturewas cooled to ambient temperature and concentrated at reduced pressure.The resulting mixture was purified by column chromatography through asilica gel cartridge (12 g) eluting with ethyl acetate/hexane (1:9 to1:2) to give the product as a light yellow solid. ¹H NMR (300 MHz, DMSO)δ=8.02 (dd, J=1.5, 7.9 Hz, 1H), 7.87 (dd, J=1.5, 7.6 Hz, 1H), 7.67 (t,J=7.9 Hz, 1H), 7.36 (m, 3H), 7.31-7.19 (m, 2H), 7.01 (br s, 2H), 6.86(t, J=2.1 Hz, 2H), 6.26 (t, J=2.1 Hz, 2H). MS (ES⁺)=323 (MH)⁺.

Example 153: Synthesis ofN-Acetyl-3-phenylethynyl-2-pyrrol-1-yl-benzenesulfonamide

N-Acetyl-3-bromo-2-pyrrol-1-yl-benzenesulfonamide: To a slurry of aceticacid (9.6 mg, 0.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (31 mg, 0.16 mmol), and 4-dimethylaminopyridine (20 mg,0.16 mmol) in N,N-dimethylformamide (0.20 mL) was added3-bromo-2-pyrrol-1-yl-benzenesulfonamide (40 mg, 0.13 mmol). Theresulting mixture was stirred at ambient temperature for 16 hours. Thereaction mixture was then diluted with aqueous hydrochloric acid (0.1N,10 mL) and extracted with ethyl acetate (2×15 mL). The combined organicextracts were dried with magnesium sulfate, filtered and concentrated atreduced pressure to give the product in quantitative yield, which wasused in the next step without purification.

N-Acetyl-3-phenylethynyl-2-pyrrol-1-yl-benzenesulfonamide: To a degassedsolution of N-Acetyl-3-bromo-2-pyrrol-1-yl-benzenesulfonamide (40 mg,0.117 mmol) in triethylamine (0.40 mL), phenylacetylene (24 mg, 26 μL,0.23 mmol) and copper (I) iodide (1.1 mg, 0.0058 mmol) in a sealed tubewas added bis(triphenylphosphine)palladium(II) dichloride (8.2 mg,0.00117 mmol). The tube was sealed and heated at 90° C. for 48 hours.The reaction mixture was cooled to ambient temperature and concentratedat reduced pressure. The resulting mixture was purified by columnchromatography through a silica gel cartridge (4 g) eluting with ethylacetate/hexane (1:4 to 1:2) to give the product as a white foam. ¹H NMR(300 MHz, DMSO) δ=11.74 (br s, 1H), 8.10 (dd, J=1.5, 7.9 Hz, 1H), 7.94(dd, J=1.5, 7.6 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.44-7.19 (m, 5H), 6.82(t, J=2.2 Hz, 2H), 6.30 (t, J=2.1 Hz, 2H), 1.84 (s, 3H). MS (ES)=365(MH)⁺.

Example 154: Synthesis of2-(dimethyl-1,2-oxazol-4-yl)-3-(2-phenylethynyl)benzoic acid

Acetic acid 2-bromo-6-cyano-phenyl ester: At 0° C. to a solution of2-bromo-6-cyano-phenol (2 g, 10.1 mmol) and triethylamine (2.25 mL, 16.2mmol) in dichloromethane (30 mL) was slowly added acetyl chloride (1 Min dichloromethane, 13.1 mL, 13.1 mmol). The reaction mixture wasstirred at room temperature for 30 minutes, washed with water, dried(anhydrous sodium sulfate), concentrated and purified by columnchromatography through a silica gel cartridge (40 g) eluting with ethylacetate/hexane (0-20%) to give the product as a white solid.

Acetic acid 2-cyano-6-phenylethynyl-phenyl ester: To a sealed flask wasloaded a mixture of acetic acid 2-bromo-6-cyano-phenyl ester (1.6 g,6.67 mmol), bis(triphenylphosphine)palladium(II) dichloride (468 mg,0.667 mmol), copper iodide (127 mg, 0.667 mmol) andN,N-diisopropylethylamine (1.74 mL, 10 mmol). The mixture was degassedwith N₂ for 10 minutes, phenylacetylene (1 g, 10 mmol) was added and themixture was degassed with N₂ for 5 minutes. The reaction mixture washeated at 90° C. for 3 hours. After cooling to ambient temperature, thecrude mixture was filtered through celite and washed withdichloromethane. The filtrate was concentrated and purified by columnchromatography through a silica gel cartridge (40 g) eluting with ethylacetate/hexane (0-20%) to give the product as a white solid.

2-Hydroxy-3-phenylethynyl-benzonitrile: To a solution of acetic acid2-cyano-6-phenylethynyl-phenyl ester (1.9 g, 8.68 mmol) intetrahydrofuran (3 mL) was added ammonium hydroxide (3 mL). The reactionmixture was stirred at room temperature for 30 minutes, acidified with 4N hydrochloric acid in water and extracted with ethyl acetate (15 mL×3).The combined organic extracts were dried (anhydrous sodium sulfate),concentrated and vacuum dry to give the product as a white solid.

Trifluoro-methanesulfonic acid 2-cyano-6-phenylethynyl-phenyl ester: Toa solution of 2-hydroxy-3-phenylethynyl-benzonitrile (800 mg, 3.64 mmol)in dichloromethane (20 mL) cooled at −70° C. was added triethylamine(0.76 mL, 5.46 mmol) followed by trifluoromethanesulfonic anhydride(0.67 mL, 4 mmol). The reaction mixture was allowed to be slowly warmedup to room temperature and stirred at room temperature for 30 minutes.Dichloromethane (20 mL) was added and the solution was washed withwater, dried (anhydrous sodium sulfate), concentrated and purified bycolumn chromatography through a silica gel cartridge (40 g) eluting withethyl acetate/hexane (0-20%) to give the product as a white solid.

2-(Dimethyl-1,2-oxazol-4-yl)-3-(2-phenylethynyl)benzoic acid: A mixtureof trifluoro-methanesulfonic acid 2-cyano-6-phenylethynyl-phenyl ester(50 mg, 0.143 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole(48 mg, 0.215 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (10.5 mg,0.014 mmol) and potassium carbonate (39.5 mg, 0.286 mmol) in 1,4-dioxane(0.5 mL) and water (0.5 mL) was degassed with N₂ for 10 minutes andheated at 90° C. for 17 hours. After cooling down the reaction mixturewas partitioned between water and ethyl acetate, the organic layer wasdried (sodium sulfate), filtered, concentrated and purified throughpreparative thin layer chromatography to give a solid intermediate. Tothis intermediate in dimethylsulfoxide (0.5 mL) was added sodiumhydroxide solution (10% in water, 0.5 mL) and the solution was heated at100° C. for 24 hours. 1 N hydrochloric acid aqueous solution was addeddropwise until pH=1 and the reaction mixture was purified throughpreparative HPLC to give the product as a white solid. ¹H NMR (300 MHz,CDCl₃) δ=8.06-7.98 (m, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.8 Hz,1H), 7.32-7.24 (m, 5H), 2.24 (s, 3H), 2.13 (s, 3H). LCMS (ESI) m/z 318.0(M+1)⁺.

Example 155: Synthesis of 2-(benzyloxy)-3-(2-phenylethynyl)benzoic acid

2-Benzyloxy-3-phenylethynyl-benzonitrile: To a solution of2-hydroxy-3-phenylethynyl-benzonitrile (50 mg, 0.227 mmol), benzylalcohol (37 mg, 0.34 mmol) and triphenylphosphine (71.4 mg, 0.272 mmol)in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate(0.055 mL, 0.272 mmol) and the reaction mixture was stirred at roomtemperature for 17 hours. The solution was concentrated and the residuewas purified by column chromatography through a silica gel cartridge (12g) eluting with ethyl acetate/hexane (0-20%) to give the product as awhite solid.

2-(benzyloxy)-3-(2-phenylethynyl)benzoic acid: To2-benzyloxy-3-phenylethynyl-benzonitrile (40 mg, 0.129 mmol) indimethylsulfoxide (0.5 mL) was added sodium hydroxide solution (10% inwater, 0.5 mL) and the solution was heated at 100° C. for 24 h. 1 Nhydrochloric acid aqueous solution was added dropwise until pH=1 and thereaction mixture was purified through preparative HPLC to give the pureproduct as a white solid. ¹H NMR (300 MHz, CDCl₃) δ=8.06 (d, J=6.7 Hz,1H), 7.77 (d, J=7.6 Hz, 1H), 7.55-7.44 (m, 4H), 7.43-7.23 (m, 7H), 5.45(s, 2H). LCMS (ESI) m/z 329.0 (M+1)⁺.

Example 156: Synthesis of2-[3-(methoxycarbonyl)-1H-indol-6-yl]-3-(2-phenylethynyl)benzoic acid

2-[3-(methoxycarbonyl)-1H-indol-6-yl]-3-(2-phenylethynyl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,DMSO) δ 12.00 (s, 1H), 8.13 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H),7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.71 (dd, J=7.8, 1.4 Hz, 1H), 7.54-7.39(m, 2H), 7.33-7.21 (m, 3H), 7.18 (dd, J=8.2, 1.5 Hz, 1H), 7.12-7.05 (m,2H), 3.81 (s, 3H). MS m/z (M+H) 396.0.

Example 157: Synthesis of3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid

Methyl 2-bromo-3-nitrobenzoate: To a stirring solution of2-bromo-3-nitrobenzoic acid (500 mg, 2.04 mmol) in methanol (5 mL) wasadded concentrated sulfuric acid (0.5 mL). The resulting solution washeated at 80° C. for 18 hours. The reaction mixture was cooled toambient temperature and concentrated at reduced pressure. The residuewas diluted with ethyl acetate (50 mL) and washed with 1N aqueous sodiumhydroxide solution (50 mL) and brine, dried (magnesium sulfate),filtered and concentrated at reduced pressure to give the desiredproduct as a colorless oil which was used in the next step withoutfurther purification.

Methyl 2-phenyl-3-nitrobenzoate: To a mixture of methyl2-bromo-3-nitrobenzoate (2.6 g, 10 mmol), phenyl boronic acid (1.46 g,12 mmol) and palladium acetate (171 mg, 0.7 mmol) in acetone (12 mL) wasadded 2N aqueous potassium carbonate (12 mL). The reaction mixture washeated at 65° C. for 4 hours, cooled to ambient temperature andpartitioned between ethyl acetate (200 mL) and water (100 mL). Theorganic layer was dried (magnesium sulfate), concentrated and purifiedby column chromatography through a silica gel cartridge (80 g) elutingwith ethyl acetate/hexane (0 to 5%) to achieve the product as a solid.¹H NMR (300 MHz, CDCl₃) δ=7.99 (dd, J=1.2, 7.9 Hz, 1H), 7.88 (dd, J=1.3,8.1 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.44-7.35 (m, 3H), 7.27-7.19 (m,2H), 3.57 (s, 3H).

Methyl 2-phenyl-3-aminobenzoate: To a stirring solution of methyl2-phenyl-3-nitrobenzoate (1.09 g, 4.24 mmol) in a mixture of acetic acid(4 mL) and methanol (10 mL) was added zinc powder (1.38 g, 21.2 mmol) inthree portions. The resulting mixture was stirred at ambient temperaturefor 18 hours. The mixture was neutralized by 6N aqueous sodium hydroxidesolution, extracted with ethyl acetate (3×100 mL). The organic layer waswashed with brine, dried (magnesium sulfate) and concentrated at reducedpressure to give the product as a yellow solid which was used in thenext step without further purification.

Methyl 2-phenyl-3-iodobenzoate: To a solution of methyl2-phenyl-3-aminobenzoate (2.29 g, 10 mmol) in 1,4-dioxane (30 mL) andwater (20 mL) at 0° C. was added concentrated hydrochloric acid (3.0mL). After 25 minutes, aqueous sodium nitrate solution (760 mg, 7.4mmol, 10 mL water) was added and the resulting mixture was stirred for 1hour. Potassium iodide solution (14.9 g, 90 mmol, 10 mL water) was addedvia addition funnel. The resulting mixture was allowed to warm toambient temperature and stirred for 18 hours. The reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with sodium hydroxidesolution (100 mL, 2N), followed by saturated aqueous sodium thiosulfatesolution (50 mL). The organic layer was dried (magnesium sulfate),concentrated and purified by column chromatography through a silica gelcartridge (80 g) eluting with ethyl acetate/hexane (0 to 5%) to providethe product as a red oil (2.33 g, 68%, 70% pure) ¹H NMR (300 MHz, CDCl₃)δ=8.08 (dd, J=1.2, 7.9 Hz, 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.44-7.29(m, 3H), 7.18-7.07 (m, 2H), 3.54-3.51 (m, 3H). MS (ES⁺)=177 (M-31)⁺

Methyl 2-phenyl-3-(3-hydroxyprop-1-ynyl)benzoate: To a sealed flask wasadded methyl 2-phenyl-3-iodobenzoate (734 mg, 2.17 mmol), triethylamine(3 mL) and N,N-dimethylformamide (7 mL). The mixture was degased for 30minutes, followed by addition of bis(triphenylphosphine)palladium(II)dichloride (151 mg, 0.22 mmol), copper(I) iodide (21 mg, 0.11 mmol) andpropargyl alcohol (0.26 mL, 4.34 mmol). The flask was sealed and heatedat 45° C. for 18 hours. After cooling to ambient temperature, themixture was poured into water (150 ml), extracted with ethyl acetate(3×100 mL). The organic layer was dried (magnesium sulfate),concentrated and purified by column chromatography through a silica gelcartridge (40 g) eluting with ethyl acetate/hexane (10% to 20%) toprovide the product as a red oil. ¹H NMR (300 MHz, CDCl₃) δ=7.78 (dd,J=1.5, 7.9 Hz, 1H), 7.63 (dd, J=1.3, 7.8 Hz, 1H), 7.41-7.26 (m, 5H),4.20 (d, J=5.0 Hz, 2H), 3.56 (s, 3H).

Methyl 2-phenyl-3-(3-bromoprop-1-ynyl)benzoate: To a solution of methyl2-phenyl-3-(3-hydroxyprop-1-ynyl)benzoate (100 mg, 0.376 mmol) indichloromethane (1 mL), carbon tetrabromide (157 mg, 0.564 mmol) wasadded and the reaction mixture was cooled to 0° C., the solution oftriphenyl phosphine (128 mg, 0.583 mmol) in dichloromethane (0.5 mL) wasadded drop wisely. The mixture warmed to ambient temperature and stirredfor 3 hours. Ethanol (0.2 mL) was added. After 25 minutes, the mixturewas concentrated and purified by column chromatography through a silicagel cartridge (4 g) eluting with ethyl acetate/hexane (0 to 5%) toachieve the product as a colored oil.

3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid methyl ester: Toa mixture of benzylamine (24 mg, 0.226 mmol) and cesium carbonate (92mg, 0.282 mmol) in acetonitrile (1 mL) was added methyl2-phenyl-3-(3-bromoprop-1-ynyl)benzoate (37 mg, 0.113 mmol) and themixture was stirred at ambient temperature for 18 hours. The reactionmixture was filtered, concentrated and purified by column chromatographythrough a silica gel cartridge (4 g) eluting with ethyl acetate/hexane(0 to 10%) to achieve the product as a solid. MS (ES⁺)=356 (MH⁺).

3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid: To a mixture of3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid methyl ester (29mg, 0.082 mmol) in tetrahydrofuran (0.2 mL), methanol (0.2 mL) and water(0.2 mL) was added lithium hydroxide (10 mg, 0.4 mmol) and stirred for18 hrs. The mixture was neutralized with hydrochloric acid (2N) to pH=4and concentrated at reduced pressure. The crude product was purified bypreparative HPLC to give the product as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ=7.84 (ddd, J=1.3, 7.8, 9.4 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H),7.53-7.33 (m, 10H), 4.02 (s, 2H), 3.86 (s, 2H). MS (ES⁺)=342 (MH⁺).

Example 158: Synthesis of3-(3-{[3-(1H-imidazol-1-yl)propyl]amino}prop-1-yn-1-yl)-2-phenylbenzoicacid

3-(3-{[3-(1H-imidazol-1-yl)propyl]amino}prop-1-yn-1-yl)-2-phenylbenzoicacid was prepared by the same procedure as example 157. ¹H NMR (300 MHz,DMSO-d₆) δ=8.98 (s, 1H), 7.79-7.64 (m, 4H), 7.51 (t, J=7.7 Hz, 1H),7.43-7.33 (m, 3H), 7.27-7.24 (m, 2H), 4.19 (t, J=6.9 Hz, 2H), 3.99 (s,2H), 2.66 (d, J=7.6 Hz, 2H), 2.04 (d, J=7.3 Hz, 2H). MS (ES⁺)=359.99(MH⁺).

Example 159: Synthesis of2-phenyl-3-[3-(4-phenylpiperazin-1-yl)prop-1-yn-1-yl]benzoic acid

2-phenyl-3-[3-(4-phenylpiperazin-1-yl)prop-1-yn-1-yl]benzoic acid wasprepared by the same procedure as example 157. ¹H NMR (300 MHz, DMSO-d₆)δ=7.79 (dd, J=1.2, 7.6 Hz, 1H), 7.75 (dd, J=1.3, 7.8 Hz, 1H), 7.54-7.24(m, 8H), 6.99 (d, J=8.5 Hz, 2H), 6.87 (t, J=7.1 Hz, 1H), 4.18 (br. s.,2H), 3.15-2.70 (br. S., 8H). MS (ES⁺)=397.10 (MH⁺).

Example 160: Synthesis of2-phenyl-3-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]benzoic acid

2-phenyl-3-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]benzoic acid was preparedby the same procedure as example 157. ¹H NMR (300 MHz, DMSO-d₆) δ=7.78(dd, J=1.5, 7.6 Hz, 1H), 7.74 (dd, J=1.3, 7.8 Hz, 1H), 7.51 (t, J=7.8Hz, 1H), 7.45-7.35 (m, 3H), 7.30-7.24 (m, 2H), 4.20 (s, 2H), 3.44-3.2(br. S., 2H), 2.99-2.83 (m, 2H), 1.78 (br. s., 4H). MS (ES⁺)=306.06(MH⁺).

Example 161: Synthesis of 3-(3-hydroxyprop-1-yn-1-yl)-2-phenylbenzoicacid

3-(3-hydroxyprop-1-yn-1-yl)-2-phenylbenzoic acid was prepared by thesame procedure as example 157. ¹H NMR (300 MHz, DMSO-d₆) δ=12.75 (br.s., 1H), 7.70-7.60 (m, 2H), 7.47-7.21 (m, 6H), 5.14 (br. s., 1H), 4.04(br. s., 2H).

Example 162: Synthesis of3-{2-[3-(Aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[3-(aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid wasprepared by the same procedure as example 157. ¹H NMR (300 MHz, CD₃OD) δ7.76 (ddd, J=8.0, 6.6, 1.6 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.45-7.40(m, 3H), 7.37 (d, J=5.4 Hz, 1H), 6.93-6.73 (m, 2H), 6.35-6.08 (m, 2H),4.09 (s, 2H). MS m/z (M+) 317.1

Example 163: Synthesis of3-{2-[3-(3,5-difluorobenzenesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid

To a stirring solution of methyl3-{2-[3-(aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoate (0.1mmol) in dichloromethane (2 mL) was added 3,5-difluoro-benzenesulfonylchloride (0.15 mmol), triethylamine (0.1 g), and catalytic4-dimethylaminopyridine at 0° C. and stirred for 16 hours. The reactionmixture was then quenched with water (1 mL). The organic layers werewashed with water (1 mL), brine (1 mL) dried (sodium sulfate), filteredand concentrated under reduced pressure. The resulting crude product wasthen dissolved in terahydrofuran:methanol (1:1 mL) and added 2N sodiumhydroxide solution (0.3 mL) and stirred for 24 hours at ambienttemperature. This solution was then concentrated and neutralized to pH 4using 1 N HCl solution. The aqueous layer was then extracted using ethylacetate (2×5 mL) and washed with water (2 mL) and brine (3 mL). Theorganic layers were combined, dried (sodium sulfate), filtered andconcentrated under reduced pressure. The resulting crude product wasthen purified using reverse phase HPLC. ¹H NMR (300 MHz, CD₃OD) δ8.21-8.04 (m, 1H), 7.88 (d, J=6.4 Hz, 1H), 7.83-7.70 (m, 1H), 7.54-7.45(m, 2H), 7.33 (dd, J=6.4, 1.8 Hz, 2H), 7.26-7.06 (m, 3H), 6.86-6.79 (m,2H), 6.66-6.56 (m, 1H), 6.32-6.26 (m, 2H), 4.12 (d, J=2.5 Hz, 2H). MSm/z (M+) 493.1

Example 164: Synthesis of3-{2-[4-(1,2-dimethyl-1H-imidazole-5-sulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[4-(1,2-dimethyl-1H-imidazole-5-sulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid was prepared by the same procedure as example 163. ¹H NMR (300 MHz,CD₃OD) δ 7.76 (ddd, J=7.9, 6.3, 1.6 Hz, 1H), 7.69-7.56 (m, 2H),7.58-7.52 (m, 1H), 7.52-7.43 (m, 2H), 7.25-7.15 (m, 3H), 6.90-6.80 (m,2H), 6.33-6.19 (m, 2H), 4.20 (d, J=8.8 Hz, 2H), 3.57 (s, 3H), 2.39 (s,3H). MS m/z (M+) 475.1

Example 165: Synthesis of3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid

3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid was prepared by the same procedure as example 163. ¹H NMR (300 MHz,CD₃OD) δ 7.76 (d, J=7.8 Hz, 1H), 7.49 (dd, J=10.3, 5.3 Hz, 1H), 7.38 (d,J=6.0 Hz, 1H), 7.30 (dd, J=20.9, 13.4 Hz, 2H), 6.89-6.77 (m, 2H),6.31-6.21 (m, 2H), 4.25 (s, 2H), 2.42 (d, J=4.9 Hz, 1H), 1.10-0.74 (m,4H). MS m/z (M+) 421.1

Example 166: Synthesis of2-(3-methoxyphenyl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoicacid

2-Bromo-3-ethynyl-benzoic acid methyl ester: A solution of2-bromo-3-iodobenzoate (1 g, 2.9 mmol) and trimethylsilylacetylene (14.5mmol) in terahydrofuran:triethylamine (20 ml:20 mL) was degassed using anitrogen gas balloon for 5 minutes in a round bottom flask. To thissolution was added Bis(triphenylphosphine)palladium(II) dichloride (210mg, 0.3 mmol) and copper iodide (30 mg) and the reaction was stirred for16 hours at ambient temperature. The reaction mixture was then filteredthrough celite using ethyl acetate (50 mL). The resultant solution wasthe concentrated under reduced pressure and purified through silica gelcartridge eluting with ethyl acetate/hexanes to give the product as abrown solid in 76% yield. To a stirring solution of the brown (0.6 g) inmethanol (20 mL) was added solid potassium carbonate (20 mg) and thereaction was stirred for 16 hours at ambient temperature. The resultantmixture was concentrated and was diluted with ethyl acetate (10 mL) andwashed with water (2×5 mL), brine (2 mL), dried (sodium sulfate),filtered and concentrated under reduced pressure. The resultant crudeproduct was purified through a small silica gel cartridge eluting withethyl acetate/hexanes (1:9) to provide 2-bromo-3-ethynyl-benzoic acidmethyl ester.

ExTo a stirring solution of 2-bromo-3-ethynyl-benzoic acid methyl ester(0.5 g, 2.1 mmol) was added3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 2.3 mmol)in terahydrofuran:triethylamine (20:20 mL) and the reaction was degassedusing a nitrogen gas balloon for 15 minutes in a round bottom flask. Tothis solution was added Bis(triphenylphosphine) palladium(II) dichloride(150 mg, 0.21 mmol) and copper iodide (30 mg) and the reaction wasstirred for 16 hours at ambient temperature. The reaction mixture wasthen filtered through celite using ethyl acetate (50 mL). The resultantsolution was the concentrated under reduced pressure and purifiedthrough silica gel cartridge eluting with ethyl acetate/hnes to give theproduct as a brown solid in 54% yield.

To a stirring solution of above brown solid (0.05 g, 0.1 mmol) indimethoxyethane:water (5:0.1 mL) was added 3-methoxyphenylboronic acid(0.12 mmol), Tetrakis(triphenylphosphine) palladium(0) (12 mg, 0.01mmol) and potassium carbonate (35 mg, 0.25 mmol) in a sealed vial andthe reaction was heated to 130° C. for 10 minutes. The resultant mixturewas allowed to cool to ambient temperature and was diluted with ethylacetate (20 mL) and washed with water (2×5 mL), brine (2 mL), dried(sodium sulfate), filtered and concentrated under reduced pressure. Theresultant crude product was then dissolved in terahydrofuran:methanol(1:1 mL), 2N sodium hydroxide solution (0.3 mL) was added, and stirredfor 24 hours at ambient temperature. This solution was then concentratedand neutralized to pH 4 using 1 N hydrochloric acid solution. Theaqueous layer was then extracted using ethyl acetate (2×5 mL) and washedwith water (2 mL) and brine (3 mL). The organic layers were combined,dried (sodium sulfate), filtered and concentrated under reducedpressure. The resulting crude product was then purified using reversedphase HPLC to provide3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoicacid. ¹H NMR (300 MHz, DMSO) δ 12.08 (s, 1H), 8.24 (dd, J=4.7, 1.6 Hz,1H), 7.74-7.68 (m, 2H), 7.66 (dd, J=7.8, 1.4 Hz, 1H), 7.47 (t, J=7.7 Hz,1H), 7.41-7.31 (m, 2H), 7.07 (dd, J=7.9, 4.7 Hz, 1H), 7.01 (dd, J=7.4,2.6 Hz, 1H), 6.92 (dd, J=8.9, 1.5 Hz, 2H), 3.73 (s, 3H). MS m/z (M+H)369.0

Example 167: Synthesis of2-(1-methyl-1H-indazol-6-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoicacid

2-(1-methyl-1H-indazol-6-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared by the sameprocedure as example 166. ¹H NMR (300 MHz, DMSO) δ 12.04 (s, 1H), 8.16(dd, J=4.4, 1.9 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 7.81-7.75 (m, 2H), 7.74(q, J=1.4 Hz, 1H), 7.65 (d, J=1.1 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H),7.56-7.45 (m, 1H), 7.10 (dd, J=8.3, 1.3 Hz, 1H), 6.81-6.67 (m, 2H), 3.98(s, 3H). MS m/z (M+) 392.9

Example 168: Synthesis of2-(2-methyl-1,3-benzothiazol-5-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoicacid

2-(2-methyl-1,3-benzothiazol-5-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoicacid was prepared by the same procedure as example 166. ¹H NMR (300 MHz,DMSO) δ 12.05 (s, 1H), 8.17 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.89 (s,1H), 7.75 (d, J=9.6 Hz, 2H), 7.67 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.34(d, J=8.1 Hz, 1H), 6.83 (s, 2H), 2.77 (s, 3H). MS m/z (M+) 409.7

Example 169: Synthesis of2-(3-methoxyphenyl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(3-methoxyphenyl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO) δ9.10 (d, J=1.9 Hz, 1H), 7.84-7.70 (m, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.34(m, 1H), 7.00-6.87 (m, 3H), 3.76 (s, 3H). MS m/z (M+) 335.9

Example 170: Synthesis of2-(1-methyl-1H-indazol-6-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(1-methyl-1H-indazol-6-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acidwas prepared by the same procedure as example 169. ¹H NMR (300 MHz,DMSO) δ 9.04 (d, J=1.9 Hz, 1H), 8.75 (s, 1H), 8.06 (d, J=0.8 Hz, 1H),7.84 (dt, J=7.8, 4.1 Hz, 1H), 7.77 (dd, J=7.9, 1.3 Hz, 2H), 7.46-7.28(m, 2H), 7.27-7.18 (m, 2H), 3.91 (s, 3H). MS m/z (M+) 359.4

Example 171: Synthesis of2-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acidwas prepared by the same procedure as example 169. ¹H NMR (300 MHz,DMSO) δ 9.06 (d, J=2.0 Hz, 1H), 7.78 (dd, J=7.7, 1.4 Hz, 1H), 7.74-7.65(m, 2H), 7.55-7.52 (m, 1H), 7.48 (t, J=7.7 Hz, 2H), 7.35 (d, J=3.1 Hz,1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 6.46 (dd, J=3.1, 0.8 Hz, 1H), 3.82(s, 3H). MS m/z (M+) 358.9

Example 172: Synthesis of2-(pyridin-4-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(pyridin-4-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid wasprepared by the same procedure as example 169. ¹H NMR (300 MHz, DMSO) δ9.10 (d, J=1.9 Hz, 1H), 8.85 (s, 1H), 8.03 (dd, J=7.8, 1.2 Hz, 1H), 7.95(dd, J=7.8, 1.3 Hz, 1H), 7.81 (dd, J=5.7, 3.9 Hz, 4H), 7.68 (t, J=7.8Hz, 1H). MS m/z (M+) 306.9

Example 173: Synthesis of2-(2-methyl-1,3-benzothiazol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoicacid

2-(2-methyl-1,3-benzothiazol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoicacid was prepared by the same procedure as example 169. ¹H NMR (300 MHz,CD₃OD) δ 8.90 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.3, 0.6 Hz, 1H), 7.93-7.86(m, 2H), 7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.43 (dd,J=8.3, 1.7 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 2.85 (s, 3H). MS m/z (M+)376.8

Example 174: Synthesis of2-(1H-indol-3-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid

2-(1H-indol-3-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid was preparedby the same procedure as example 166. ¹H NMR (300 MHz, DMSO-d₆) δ=11.34(br. s., 1H), 8.47 (br. s., 2H), 7.82 (dd, J=1.3, 7.8 Hz, 1H), 7.74 (d,J=7.5 Hz, 1H), 7.51-7.43 (m, 3H), 7.33 (d, J=7.9 Hz, 1H), 7.12 (t, J=7.6Hz, 1H), 7.02-6.90 (m, 3H). MS (ES⁺)=338.93 (MH⁺).

Example 175: Synthesis of2-[4-(dimethylamino)phenyl]-3-[2-(pyridin-4-yl)ethynyl]benzoic acid

2-[4-(dimethylamino)phenyl]-3-[2-(pyridin-4-yl)ethynyl]benzoic acid wasprepared by the same procedure as example 174. ¹H NMR (300 MHz, DMSO-d6)δ=8.67 (br. s., 2H), 7.88-7.71 (m, 2H), 7.53-7.33 (m, 3H), 7.31-7.16 (m,2H), 6.86 (d, J=8.8 Hz, 2H), 2.97 (s, 6H). MS (ES⁺)=343.01 (MH⁺).

Example 176: Synthesis of2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoicacid

2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoicacid was prepared by the same procedure as example 174. MS (ES⁺)=371.00(MH⁺).

Example 177: Synthesis of 2-phenyl-3-[2-(pyridin-4-yl)ethynyl]benzoicacid

2-phenyl-3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by thesame procedure as example 174. ¹H NMR (300 MHz, DMSO-d6) δ=8.59 (d,J=5.9 Hz, 2H), 7.87-7.81 (m, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.48-7.32 (m,5H), 7.18 (d, J=5.2 Hz, 2H). MS (ES⁺)=300.01 (MH⁺).

Example 178: Synthesis of6-(3-carboxy-phenylethynyl)-1H-indole-4-carboxylic acid

6-(3-carboxy-phenylethynyl)-1H-indole-4-carboxylic acid was prepared bythe same procedure as example 90. ¹H NMR (300 MHz, DMSO) δ=11.64 (s,J=3.5, 3.5 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.94 (td, J=1.7, 8.2 Hz,1H), 7.86-7.80 (m, 3H), 7.63 (t, J=2.8 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H),6.99-6.96 (m, 1H). MS (ESI) m/z 287.9 (M−H₂O+1)⁺.

1192

Example 179: Synthesis of 3-(4-carbamoyl-1H-indol-6-ylethynyl)-benzoicacid

6-Bromo-1H-indole-4-carboxylic acid amide: A solution of6-bromo-1H-indole-4-carboxylic acid methyl ester (600 mg, 2.36 mmol) inammonium hydroxide (10 mL) in a sealed flask was heated at 110° C. for18 hours. After cooling to ambient temperature, the precipitates werefiltered, washed with water and air dried to give 240 mg of the desiredproduct (43%) as a white solid.

3-(4-Carbamoyl-1H-indol-6-ylethynyl)-benzoic acid was prepared by thesame procedure as example 90. ¹H NMR (300 MHz, CD₃OD) δ=11.05 (br. s.,1H), 8.15 (t, J=1.5 Hz, 1H), 7.99 (td, J=1.4, 7.9 Hz, 1H), 7.78-7.72 (m,2H), 7.68 (s, 1H), 7.53-7.47 (m, 2H), 6.95-6.92 (m, 1H). MS (ESI) m/z305.0 (M+1)⁺.

Example 180: Synthesis of 3-(3-carbamoyl-phenylethynyl)-benzoic acid

3-(3-Carbamoyl-phenylethynyl)-benzoic acid was prepared by the sameprocedure as example 90. ¹H NMR (300 MHz, DMSO) δ=13.25 (br. s., 1H),8.11-8.05 (m, 3H), 7.98 (td, J=1.5, 11.0 Hz, 2H), 7.95-7.88 (m, 1H),7.80 (d, J=7.5 Hz, 1H), 7.73 (td, J=1.4, 7.8 Hz, 1H), 7.60-7.46 (m, 2H).MS (ESI) m/z 266.1 (M+1)⁺.

Example 181: Synthesis of3-(1-benzenesulfonyl-1H-indol-3-ylethynyl)-benzoic acid

3-(1-Benzenesulfonyl-1H-indol-3-ylethynyl)-benzoic acid was prepared bythe same procedure as example 90. ¹H NMR (300 MHz, CDCl₃) δ=9.75 (br.s., 1H), 8.24 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.82 (d, J=6.7 Hz, 1H),7.74 (d, J=7.6 Hz, 1H), 7.68-7.56 (m, 2H), 7.53-7.40 (m, 5H), 7.30-7.19(m, 3H).

Example 182: Synthesis of 3-(1H-indol-3-ylethynyl)-benzoic acid

3-(1H-Indol-3-ylethynyl)-benzoic acid was prepared by the same procedureas example 90. ¹H NMR (300 MHz, CD₃OD) δ=8.32 (s, 1H), 8.22 (d, J=7.2Hz, 1H), 8.07-7.98 (m, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.9 Hz,1H), 7.48-7.38 (m, 2H), 7.26-7.16 (m, 2H).

Example 183

Synthesis of 3-(3-carboxy-phenylethynyl)-benzoic acid methyl ester3-(3-Methoxycarbonyl-phenylethynyl)-benzoic acid tert-butyl ester wasprepared by the same procedure as example 90 and was used withoutfurther purification.

3-(3-Carboxy-phenylethynyl)-benzoic acid methyl ester: To a solution of3-(3-methoxycarbonyl-phenylethynyl)-benzoic acid tert-butyl ester (690mg, 2.05 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid(5 mL). The solution was stirred at room temperature for 1 hour,concentrated and dried over vacuum to give 570 mg of the product (99%)as a white solid. ¹H NMR (300 MHz, CDCl₃) δ=8.24 (d, J=7.0 Hz, 2H), 8.04(t, J=6.8 Hz, 2H), 7.73 (t, J=4.0 Hz, 2H), 7.46 (t, J=7.8 Hz, 2H), 3.96(s, 3H). MS (ESI) m/z 281.0 (M+1)⁺.

Example 184: Synthesis of3-(3-carbamoyl-5-methoxy-phenylethynyl)-benzoic acid

3-(3-Carbamoyl-5-methoxy-phenylethynyl)-benzoic acid was prepared by thesame procedure as example 90. ¹H NMR (300 MHz, CD₃OD) δ=8.15-8.12 (m,1H), 8.04-8.00 (m, 1H), 7.76-7.72 (m, 1H), 7.64 (s, 1H), 7.54-7.45 (m,2H), 7.35-7.25 (m, 1H), 3.88 (s, 3H). MS (ESI) m/z 296.1 (M+1)⁺.

Example 185: Synthesis of3′-hydroxy-4′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acid

2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol: Amixture of 5-bromo-2-methoxy-phenol (300 mg, 1.48 mmol),bis(pinacolato)diboron (488 mg, 1.92 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (60 mg,0.074 mmol) and potassium acetate (278 mg, 3 mmol) in dimethylformamide(4 mL) was heated at 90° C. for 18 hours. After cooling to roomtemperature, the reaction mixture was partitioned between dichlomethane(50 mL) and water (30 mL). The organic layer was dried (sodium sulfate),filtered, concentrated and purified through silica gel cartridge elutingwith ethyl acetate/hexanes to give the product as a white solid in 86%yield.

3′-Hydroxy-4′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acidwas prepared from2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol by thesame procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=8.45 (br. s.,2H), 7.75 (t, J=7.9 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.26-7.15 (m, 2H),7.00-6.87 (m, 2H), 6.79 (dd, J=1.8, 8.2 Hz, 1H), 3.90 (s, 3H). MS (ESI)m/z 346.13 (M+1)⁺.

Example 186: Synthesis of5′-hydroxy-3′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acid

5′-Hydroxy-3′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ=8.46 (br. s., 2H), 7.79 (dd, J=1.2, 7.6 Hz, 1H), 7.75 (dd,J=1.2, 7.9 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.20 (d, J=5.3 Hz, 2H),6.47-6.38 (m, 3H), 3.75 (s, 3H). MS (ESI) m/z 346.1 (M+1)⁺.

Example 187: Synthesis of2-(1H-pyrazol-3-yl)-3-pyridin-4-ylethynyl-benzoic acid

2-(1H-Pyrazol-3-yl)-3-pyridin-4-ylethynyl-benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ=8.82-8.73(m, 2H), 8.58-8.53 (m, 2H), 8.34 (d, J=7.3 Hz, 1H), 8.07 (d, J=7.3 Hz,1H), 7.91 (d, J=2.1 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.41 (s, 1H), 6.94(d, J=1.7 Hz, 1H). MS (ESI) m/z 290.1 (M+1)⁺.

Example 188: Synthesis of2-(1H-pyrazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid

2-(1H-Pyrazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ=7.82-7.76(m, 4H), 7.68-7.64 (m, 1H), 7.50-7.42 (m, 3H). MS (ESI) m/z 290.1(M+1)⁺.

Example 189: Synthesis of2-(3,5-dimethyl-isoxazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid

2-(3,5-Dimethyl-isoxazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=8.78 (br. s., 2H), 8.16 (d, J=7.9 Hz, 1H), 7.99 (dd, J=1.2, 7.9 Hz,1H), 7.79-7.63 (m, 3H), 2.23 (s, 3H), 2.09 (s, 3H). MS (ESI) m/z 319.1(M+1)⁺.

Example 190: Synthesis of3-phenylethynyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzoic acid

3-Phenylethynyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=7.94 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H),7.38-7.20 (m, 5H), 3.87 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H). MS (ESI)m/z 331.1 (M+1)⁺.

Example 191: Synthesis of2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-methyl-but-1-ynyl)-benzoicacid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-methyl-but-1-ynyl)-benzoicacid was prepared by the same procedure as example 21. ¹H NMR (300 MHz,CDCl₃) δ=8.01 (dd, J=1.6, 7.8 Hz, 1H), 7.64 (dd, J=1.6, 7.8 Hz, 1H),7.48 (t, J=7.7 Hz, 1H), 5.90 (s, 2H), 1.92 (s, 6H), 1.38 (s, 6H). MS(ESI) m/z 280.1 (M−H₂O+1)⁺.

Example 192: Synthesis of2-(2,5-dimethyl-pyrrol-1-yl)-3-pyridin-4-ylethynyl-benzoic acid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-pyridin-4-ylethynyl-benzoic acid wasprepared by the same procedure as example 21. ¹H NMR (300 MHz, CD₃OD)δ=8.69 (br. s., 2H), 8.05 (dd, J=1.5, 7.9 Hz, 1H), 7.93 (dd, J=1.5, 7.9Hz, 1H), 7.71-7.57 (m, 3H), 5.89 (s, 2H), 1.93 (s, 6H). MS (ESI) m/z317.1 (M+1)⁺.

Example 193: Synthesis of3-(3-carbamoyl-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid

3-(3-Carbamoyl-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acidwas prepared by the same procedure as example 21. ¹H NMR (300 MHz,CD₃OD) δ=7.99-7.77 (m, 4H), 7.63-7.50 (m, 1H), 7.48-7.32 (m, 2H), 5.85(s, 2H), 1.94 (s, 6H). MS (ESI) m/z 359.0 (M+1)⁺.

Example 194: Synthesis of3-(3-carboxy-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid

3-(3-Carboxy-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acidwas prepared by the same procedure as example 21. ¹H NMR (300 MHz,CD₃OD) δ=7.98-7.78 (m, 4H), 7.64-7.50 (m, 1H), 7.50-7.33 (m, 2H), 5.85(s, 2H), 1.94 (s, 6H). MS (ESI) m/z 360.0 (M+1)⁺.

Example 195: Synthesis of2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxymethyl-phenylethynyl)-benzoicacid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-hydroxymethyl-phenylethynyl)-benzoicacid was prepared by the same procedure as example 21. ¹H NMR (300 MHz,CD₃OD) δ=7.85 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.36-7.13 (m, 4H), 5.84 (s, 2H), 4.55 (s, 2H), 1.94 (s, 6H). MS(ESI) m/z 346.0 (M+1)⁺.

Example 196: Synthesis of2-(2,5-dimethyl-pyrrol-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-ylethynyl)-benzoicacid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-ylethynyl)-benzoicacid was prepared by the same procedure as example 21. ¹H NMR (300 MHz,CD₃OD) δ=8.34 (br. s., 1H), 8.10 (dd, J=1.5, 7.9 Hz, 1H), 7.89-7.78 (m,2H), 7.70 (s, 1H), 7.64-7.49 (m, 1H), 7.35 (dd, J=5.3, 7.9 Hz, 1H), 5.90(s, 2H), 1.97 (s, 6H). MS (ESI) m/z 356.1 (M+1)⁺.

Example 197: Synthesis of2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-phenyl-prop-1-ynyl)-benzoicacid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-phenyl-prop-1-ynyl)-benzoicacid was prepared by the same procedure as example 21. ¹H NMR (300 MHz,CD₃OD) δ=8.08 (d, J=7.9 Hz, 1H), 7.97-7.85 (m, 2H), 7.68-7.42 (m, 3H),7.21 (d, J=16.1 Hz, 1H), 6.85 (d, J=15.8 Hz, 1H), 5.91 (s, 2H), 3.30 (s,1H), 1.87 (s, 6H). MS (ESI) m/z 346.0 (M+1)⁺.

Example 198: Synthesis of3-(3-acetylamino-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoicacid

3-(3-Acetylamino-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoicacid was prepared by the same procedure as example 21. ¹H NMR (300 MHz,CD₃OD) δ=7.84 (d, J=5.9 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.60-7.43 (m,3H), 7.30-7.14 (m, 1H), 6.97 (d, J=7.3 Hz, 1H), 2.12 (s, 3H), 1.95 (s,6H). MS (ESI) m/z 373.0 (M+1)⁺.

Example 199: Synthesis of3-cyclopropylethynyl-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid

3-Cyclopropylethynyl-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid wasprepared by the same procedure as example 21. ¹H NMR (300 MHz, CD₃OD)δ=7.79 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.9 Hz,1H), 5.72 (s, 2H), 1.85 (s, 6H), 1.36-1.13 (m, 1H), 0.75-0.63 (m, 2H),0.62-0.37 (m, 2H). MS (ESI) m/z 280.1 (M+1)⁺.

Example 200: Synthesis of2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-methoxy-phenylethynyl)-benzoic acid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-methoxy-phenylethynyl)-benzoic acidwas prepared by the same procedure as example 21. ¹H NMR (300 MHz, DMSO)δ=7.81 (d, J=7.9 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.24 (t, J=8.0 Hz,1H), 6.94 (d, J=2.6 Hz, 1H), 6.90 (d, J=2.6 Hz, 1H), 6.84-6.80 (m, 1H),5.80 (s, 2H), 3.72 (s, 3H), 1.82 (s, 6H). MS (ESI) m/z 346.0 (M+1)⁺.

Example 201: Synthesis of 2-(1H-indazol-6-yl)-3-phenylethynyl-benzoicacid

2-(1H-Indazol-6-yl)-3-phenylethynyl-benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=8.10 (s, 1H),7.85-7.74 (m, 3H), 7.55-7.45 (m, 2H), 7.25-7.13 (m, 4H), 6.96 (d, J=7.0Hz, 2H). MS (ESI) m/z 339.0 (M+1)⁺.

Example 202: Synthesis of2-benzo[1,3]dioxol-5-yl-3-phenylethynyl-benzoic acid

2-Benzo[1,3]dioxol-5-yl-3-phenylethynyl-benzoic acid was prepared by thesame procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=7.72 (t, J=8.5Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.31-7.19 (m, 5H), 6.87 (s, 1H), 6.88(d, J=8.2 Hz, 1H), 6.82-6.78 (m, 1H), 6.00 (s, 2H). MS (ESI) m/z 325.0(M−H₂O+1)⁺.

Example 203: Synthesis of 2-isoquinolin-6-yl-3-phenylethynyl-benzoicacid

2-Isoquinolin-6-yl-3-phenylethynyl-benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=9.78 (br. s., 1H),8.52 (d, J=8.5 Hz, 1H), 8.22-8.02 (m, 3H), 7.94 (d, J=7.3 Hz, 1H), 7.85(br. s., 1H), 7.71 (t, J=7.8 Hz, 1H), 7.24-7.10 (m, 5H), 6.72 (d, J=7.0Hz, 2H). MS (ESI) m/z 350.0 (M+1)⁺.

Example 204: Synthesis of 2-benzofuran-2-yl-3-phenylethynyl-benzoic acid

2-Benzofuran-2-yl-3-phenylethynyl-benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=7.90-7.78 (m, 2H),7.70-7.65 (m, 1H), 7.58-7.48 (m, 2H), 7.35-7.22 (m, 7H), 7.18 (s, 1H).MS (ESI) m/z 339.0 (M+1)⁺.

Example 205: Synthesis of 3-phenylethynyl-2-quinolin-8-yl-benzoic acid

3-Phenylethynyl-2-quinolin-8-yl-benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=9.14 (dd, J=1.6, 8.4Hz, 1H), 8.95 (dd, J=1.6, 5.1 Hz, 1H), 8.35 (dd, J=1.5, 8.2 Hz, 1H),8.20 (d, J=7.9 Hz, 1H), 8.03-7.90 (m, 4H), 7.73 (t, J=7.8 Hz, 1H),7.24-7.10 (m, 3H), 6.70 (d, J=7.5 Hz, 2H). MS (ESI) m/z 350.0 (M+1)⁺.

Example 206: Synthesis of2-(2-amino-pyrimidin-5-yl)-3-phenylethynyl-benzoic acid

2-(2-Amino-pyrimidin-5-yl)-3-phenylethynyl-benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ=8.47 (s,2H), 8.07 (dd, J=1.5, 7.9 Hz, 1H), 7.86 (dd, J=1.3, 7.8 Hz, 1H), 7.58(t, J=7.8 Hz, 1H), 7.37-7.29 (m, 5H). MS (ESI) m/z 316.0 (M+1)⁺.

Example 207: Synthesis of4′-dimethylaminomethyl-6-phenylethynyl-biphenyl-2-carboxylic acid

4′-Dimethylaminomethyl-6-phenylethynyl-biphenyl-2-carboxylic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD)δ=7.90 (dd, J=1.2, 7.9 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.58-7.44 (m,5H), 7.34-7.09 (m, 5H), 4.39 (s, 2H), 2.85 (m, 6H). MS (ESI) m/z 356.1(M+1)⁺.

Example 208: Synthesis of3-(4-amino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid

3-(4-Amino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ=8.24 (d,J=8.8 Hz, 1H), 8.00 (br. s., 1H), 7.93 (d, J=7.9 Hz, 1H), 7.86-7.80 (m,2H), 7.62 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.43-7.36 (m, 2H), 7.07-6.95(m, 3H), 6.61 (dd, J=2.2, 2.9 Hz, 1H). MS (ESI) m/z 353.1 (M+1)⁺.

Example 209

Synthesis of 3-(4-carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid2-Bromo-3-[4-(2-oxo-2-phenyl-ethoxycarbonyl)-phenylethynyl]-benzoic acidmethyl ester was prepared by the same Sonogashira Coupling procedure aspreparing 2-bromo-3-phenylethynyl-benzoic acid methyl ester in example119 and was used in the next step without purification.

2-(1H-Indol-6-yl)-3-[4-(2-oxo-2-phenyl-ethoxycarbonyl)-phenylethynyl]-benzoicacid methyl ester was prepared by the same Suzuki Coupling procedure aspreparing 2-(1H-indol-6-yl)-3-phenylethynyl-benzoic acid methyl ester inexample 119 and was used in the next step without purification.

3-(4-Carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid was preparedfrom 22-(1H-indol-6-yl)-3-phenylethynyl-benzoic acid methyl ester by thesame hydrolysis procedure as example 119. ¹H NMR (300 MHz, CDCl₃)δ=7.87-7.65 (m, 5H), 7.45-7.38 (m, 2H), 7.25 (d, J=3.2 Hz, 1H), 7.19(dd, J=1.5, 8.2 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.57 (d, J=3.3 Hz, 1H).MS (ESI) m/z 382.0 (M+1)⁺.

Example 210: Synthesis of2-(1H-indol-6-yl)-3-(4-methoxy-phenylethynyl)-benzoic acid

2-(1H-Indol-6-yl)-3-(4-methoxy-phenylethynyl)-benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ =7.69(d, J=7.9 Hz, 2H), 7.59 (d, J=8.2 Hz, 1H), 7.45-7.27 (m, 2H), 7.28 (d,J=3.2 Hz, 1H), 7.05 (dd, J=1.4, 8.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H),6.73 (d, J=9.1 Hz, 2H), 6.50 (d, J=3.4 Hz, 1H), 3.73 (s, 3H). MS (ESI)m/z 368.1 (M+1)⁺.

Example 211: Synthesis of3-(4-carbamoyl-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid

3-(4-Carbamoyl-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO)δ=11.21 (br. s., 1H), 8.01 (s, 1H), 7.82-7.70 (m, 4H), 7.62-7.40 (m,5H), 7.18 (d, J=8.2 Hz, 2H), 7.05 (d, J=7.0 Hz, 1H), 6.51 (s, 1H). MS(ESI) m/z 381.1 (M+1)⁺.

Example 212: Synthesis of2-(1H-indol-6-yl)-3-[4-(piperazine-1-carbonyl)-phenylethynyl]-benzoicacid

2-(1H-Indol-6-yl)-3-[4-(piperazine-1-carbonyl)-phenylethynyl]-benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ=7.78-7.74 (m, 2H), 7.60 (d, J=8.2 Hz, 1H), 7.48-7.42 (m, 2H),7.35-7.25 (m, 3H), 7.15-7.03 (m, 3H), 6.50 (d, J=3.1 Hz, 1H), 3.85-3.70(m, 4H), 3.30-3.06 (m, 4H). MS (ESI) m/z 450.3 (M+1)⁺.

Example 213: Synthesis of3-(4-acetylamino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid

3-(4-acetylamino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃)δ=7.86-7.64 (m, 3H), 7.46-7.29 (m, 4H), 7.25-7.17 (m, 2H), 7.00 (d,J=8.5 Hz, 2H), 6.56 (d, J=2.4 Hz, 1H), 2.12 (s, 3H). MS (ESI) m/z 395.1(M+1)⁺.

Example 214: Synthesis of2-(1H-indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]-phenylethynyl}-benzoicacid

2-(1H-Indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]-phenylethynyl}-benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CDCl₃) δ=9.10 (br. s., 1H), 8.75-8.69 (m, 1H), 8.43-8.37 (m, 1H),7.81-7.72 (m, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.60-7.52 (m, 3H), 7.48-7.36(m, 2H), 7.32-7.18 (m, 2H), 7.07 (d, J=7.9 Hz, 2H), 6.56 (dd, J=1.2, 3.2Hz, 1H). MS (ESI) m/z 458.0 (M+1)⁺.

Example 215: Synthesis of2-(1H-indol-6-yl)-3-(4-methanesulfonylamino-phenylethynyl)-benzoic acid

2-(1H-indol-6-yl)-3-(4-methanesulfonylamino-phenylethynyl)-benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CDCl₃) δ=7.85-7.64 (m, 3H), 7.45-7.32 (m, 2H), 7.26-7.17 (m, 2H),7.07-7.00 (m, 4H), 6.55 (dd, J=2.9 Hz, 1H), 3.46 (s, 3H). MS (ESI) m/z431.1 (M+1)⁺.

Example 216: Synthesis of2-(1H-indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)-phenylethynyl]-benzoicacid

2-(1H-Indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)-phenylethynyl]-benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CDCl₃) δ=9.10 (br. s., 1H), 8.75 (br. s., 1H), 7.77 (dd, J=1.4, 7.8 Hz,1H), 7.69 (dd, J=1.5, 7.9 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.48 (dd,J=1.5, 5.0 Hz, 1H), 7.43 (dd, J=1.2, 3.8 Hz, 1H), 7.42-7.24 (m, 2H),7.22-7.14 (m, 2H), 7.02-6.86 (m, 5H), 6.53 (dd, J=0.9, 3.2 Hz, 1H). MS(ESI) m/z 499.1 (M+1)⁺.

Example 217: Synthesis of2-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoicacid

2-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,DMSO) δ 11.89 (s, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.04 (d, J=3.0 Hz, 1H),8.00 (d, J=8.3 Hz, 1H), 7.81 (dd, J=7.7, 1.3 Hz, 1H), 7.73 (dd, J=7.8,1.4 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.48-7.44(m, 1H), 7.18 (dd, J=8.2, 1.6 Hz, 1H), 3.82 (s, 3H). MS m/z 403.5 (M+H).

Example 218: Synthesis of2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoic acid

2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d,J=2.1 Hz, 1H), 8.41 (s, 1H), 7.76 (ddd, J=7.9, 3.7, 1.4 Hz, 2H), 7.63(dd, J=13.0, 6.5 Hz, 1H), 7.45 (d, J=6.5 Hz, 1H), 7.38 (t, J=7.8 Hz,1H), 7.21-7.16 (m, 1H), 7.12 (dd, J=8.1, 1.5 Hz, 1H), 6.90 (d, J=2.0 Hz,1H), 6.56 (t, J=2.1 Hz, 1H). MS m/z 344.9 (M+H).

Example 219: Synthesis of2-(1-methyl-1H-pyrazol-4-yl)-3-(thiazol-4-ylethynyl)benzoic acid

2-(1-methyl-1H-pyrazol-4-yl)-3-(thiazol-4-ylethynyl) benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ9.16 (d, J=1.9 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.74 (dd,J=7.7, 1.4 Hz, 1H), 7.61 (dd, J=7.7, 1.4 Hz, 1H), 7.57 (d, J=0.8 Hz,1H), 7.41 (t, J=7.7 Hz, 1H), 3.89 (s, 3H). MS m/z 310.0 (M+H).

Example 220: Synthesis of3-((3-hydroxyphenyl)ethynyl)-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid

3-((3-hydroxyphenyl)ethynyl)-2-(1-methyl-1H-pyrazol-4-yl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ7.78 (s, 1H), 7.72-7.66 (m, 2H), 7.65 (d, J=0.9 Hz, 1H), 7.38(t, J=7.8 Hz, 1H), 7.21-7.10 (m, 1H), 6.86-6.77 (m, 2H), 6.75 (tt,J=2.5, 1.4 Hz, 1H), 3.96 (m, 3H). MS m/z 319.0 (M+H).

Example 221: Synthesis of2-(3-chloro-1H-indol-6-yl)-3-((3-hydroxyphenyl) ethynyl)benzoic acid

2-(3-chloro-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ12.38 (s, 1H), 9.60 (s, 1H), 7.88-7.65 (m, 3H), 7.59-7.41 (m, 2H), 7.32(s, 1H), 7.16 (dd, J=8.3, 1.5 Hz, 1H), 7.12-7.00 (m, 1H), 6.73 (d, J=9.7Hz, 1H), 6.59-6.41 (m, 2H). MS m/z 371.1 (M−OH).

Example 222: Synthesis of3-((3-hydroxyphenyl)ethynyl)-2-(1H-indazol-6-yl)benzoic acid

3-((3-hydroxyphenyl)ethynyl)-2-(1H-indazol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ8.12 (s, 1H), 7.85-7.70 (m, 4H), 7.52 (t, J=7.7 Hz, 1H), 7.45 (s, 1H),7.16-6.99 (m, 2H), 6.78-6.65 (m, 1H), 6.53-6.44 (m, 2H). MS m/z 355.0(M+H).

Example 223: Synthesis of2-(3-(2-acetamidoethyl)-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoicacid

2-(3-(2-acetamidoethyl)-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,DMSO) δ 10.90 (s, 1H), 7.93 (m, 1H), 7.72 (dd, J=7.7, 1.4 Hz, 1H), 7.64(dd, J=7.7, 1.4 Hz, 1H), 7.50 (s, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.36 (d,J=8.4 Hz, 1H), 7.18 (s, 1H), 7.13-6.98 (m, 2H), 6.74-6.64 (m, 1H),6.60-6.51 (m, 2H), 3.28 (d, J=7.7 Hz, 2H), 2.86-2.72 (m, 2H), 1.77 (s,3H). MS m/z 439.2 (M+H).

Example 224: Synthesis of3-((3-(N,N-dimethylsulfamoyl)phenyl)ethynyl)-2-fluorobenzoic acid

3-((3-(N,N-dimethylsulfamoyl)phenyl)ethynyl)-2-fluorobenzoic acid wasprepared by the same procedure as example 85. ¹H NMR (300 MHz, DMSO) δ8.02-7.87 (m, 3H), 7.87-7.81 (m, 1H), 7.81-7.69 (m, 1H), 7.63 (t, J=7.9Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 2.67 (s, 3H), 2.65 (s, 3H). MS m/z448.0 (M+H).

Example 225: Synthesis of2-(1H-indol-6-yl)-3-((4-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)benzoicacid

2-(1H-indol-6-yl)-3-((4-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.67 (d, J=7.7 Hz, 2H), 7.58 (dd, J=8.2, 0.7 Hz, 1H), 7.45-7.42(m, 1H), 7.39 (dd, J=8.1, 7.4 Hz, 1H), 7.30-7.25 (m, 1H), 7.04 (dd,J=8.1, 1.5 Hz, 1H), 6.99-6.90 (m, 2H), 6.81-6.71 (m, 2H), 6.49 (dd,J=3.1, 0.9 Hz, 1H), 4.51 (dq, J=12.0, 3.8 Hz, 21H), 4.08-3.75 (m, 2H),3.55 (ddd, J=11.7, 8.7, 3.1 Hz, 2H), 2.24-1.76 (m, 2H), 1.65 (dtd,J=12.8, 8.4, 4.0 Hz, 2H). MS m/z 438.2 (M+H).

Example 226: Synthesis of2-(1H-indol-6-yl)-3-((4-morpholinophenyl)ethynyl)benzoic acid

2-(1H-indol-6-yl)-3-((4-morpholinophenyl)ethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ8.20 (s, 1H), 7.69 (t, J=7.9 Hz, 3H), 7.43 (s, 1H), 7.36 (t, J=7.8 Hz,1H), 7.26-7.21 (m, 1H), 7.15 (dd, J=8.1, 1.4 Hz, 1H), 6.95 (d, J=8.8 Hz,2H), 6.68 (d, J=8.9 Hz, 2H), 6.60 (s, 1H), 3.92-3.71 (m, 4H), 3.20-3.02(m, 4H). MS m/z 423.1 (M+H).

Example 227: Synthesis of3-((3-carbamoylphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-carbamoylphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ13.09-12.22 (m, 1H), 11.16 (s, 1H), 7.94 (s, 1H), 7.80-7.71 (m, 2H),7.67 (dd, J=7.7, 1.4 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.7 Hz,1H), 7.43-7.39 (m, 1H), 7.39-7.29 (m, 2H), 7.21-7.14 (m, 1H), 7.04 (dd,J=8.1, 1.6 Hz, 1H), 6.56-6.32 (m, 1H). MS m/z 381.3 (M+H).

Example 228: Synthesis of3-((4-Fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((4-Fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 8.51 (s,1H), 8.37 (s, 1H), 8.06 (dd, J=7.8, 1.3 Hz, 1H), 7.87 (dd, J=7.8, 1.3Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.14-7.01 (m,2H), 7.03-6.88 (m, 2H), 6.83 (d, J=3.5 Hz, 1H). MS m/z 357.1 (M+H).

Example 229: Synthesis of3-((2,4-Difluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((2,4-Difluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.73 (dq, J=7.9, 1.4 Hz, 2H), 7.56 (dt, J=7.8, 1.8 Hz, 1H), 7.47-7.39(m, 2H), 7.29-7.22 (m, 1H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 6.97-6.82 (m,2H), 6.78 (ddd, J=10.3, 6.0, 1.3 Hz, 1H), 6.48 (dd, J=3.1, 0.9 Hz, 1H).MS m/z 374.4 (M+H).

Example 230: Synthesis of3-((3-Acetamidophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-Acetamidophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ11.17 (s, 1H), 9.96 (s, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.67 (dd,J=7.7, 1.4 Hz, 2H), 7.63-7.55 (m, 2H), 7.45 (dd, J=13.6, 5.9 Hz, 1H),7.38 (dd, J=3.3, 2.3 Hz, 2H), 7.18 (t, J=7.9 Hz, 1H), 7.05 (dd, J=8.1,1.6 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.50-6.35 (m, 1H), 2.05 (d, J=14.2Hz, 3H). MS m/z 395.0 (M+H).

Example 231: Synthesis of2-(1H-indol-6-yl)-3-((3-(nicotinamido)phenyl)ethynyl)benzoic acid

2-(1H-indol-6-yl)-3-((3-(nicotinamido)phenyl)ethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, DMSO) δ11.18 (s, 1H), 10.47 (s, 1H), 9.10 (d, J=1.6 Hz, 1H), 8.79 (dd, J=4.9,1.6 Hz, 1H), 8.41-8.13 (m, 1H), 7.79 (dd, J=7.7, 1.4 Hz, 1H), 7.75 (m,1H), 7.68 (dd, J=7.8, 1.3 Hz, 2H), 7.62 (t, J=3.6 Hz, 1H), 7.59 (s, 1H),7.48 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.39-7.35 (m, 1H), 7.28 (t, J=8.0Hz, 1H), 7.06 (dd, J=8.1, 1.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.46 (m,1H). MS m/z 458.2 (M+H).

Example 232: Synthesis of3-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoicacid

3-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CDCl₃) δ 8.39 (bs, 1H), 7.76 (m, 1H), 7.71-7.60 (m, 1H), 7.42-7.34 (m,2H), 7.24-7.14 (m, 1H), 7.12-6.96 (m, 1H), 6.97-6.83 (m, 1H), 6.80 (d,J=2.2 Hz, 1H), 6.70-6.59 (m, 2H), 6.61-6.51 (m, 2H), 6.51-6.38 (m, 2H),6.34-6.18 (m, 1H). MS m/z 545.1 (M+H).

Example 233: Synthesis of3-((3-aminophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-aminophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 8.21 (bs,1H), 7.73-7.46 (m, 3H), 7.35-7.28 (m, 2H), 7.13-7.08 (m, 1H), 7.02 (dd,J=8.1, 1.4 Hz, 1H), 6.86 (t, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.46-6.37 (m,2H), 5.94 (s, 1H).). MS m/z 353.5 (M+H).

Example 234: Synthesis of2-(1H-indol-6-yl)-3-((3-(methylsulfonamido)phenyl)ethynyl)benzoic acid

2-(1H-indol-6-yl)-3-((3-(methylsulfonamido)phenyl)ethynyl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 10.50 (s, 1H), 7.70 (ddd, J=7.9, 3.0, 1.3 Hz, 2H), 7.60 (d,J=8.2 Hz, 1H), 7.47-7.36 (m, 2H), 7.31-7.22 (m, 1H), 7.18-7.04 (m, 3H),7.01 (d, J=1.8 Hz, 1H), 6.83-6.74 (m, 1H), 6.48 (d, J=2.3 Hz, 1H),2.97-2.66 (m, 3H). MS m/z 431.0 (M+H).

Example 235: Synthesis of2-(1H-indol-6-yl)-3-((3-(thiophene-2-sulfonamido)phenyl)ethynyl)benzoicacid

2-(1H-indol-6-yl)-3-((3-(thiophene-2-sulfonamido)phenyl)ethynyl)benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,Acetone) δ 10.33 (s, 1H), 9.14 (s, 1H), 7.87-7.72 (m, 3H), 7.63 (d,J=8.1 Hz, 1H), 7.54-7.43 (m, 3H), 7.42-7.33 (m, 1H), 7.23-7.10 (m, 4H),7.05 (dd, J=5.0, 3.8 Hz, 1H), 6.85 (dd, J=4.9, 2.7 Hz, 1H), 6.53 (m,1H). MS m/z 499.8 (M+H).

Example 236: Synthesis of3-((3-acetamido-5-fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-acetamido-5-fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,DMSO) δ 11.17 (s, 1H), 10.15 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.69 (d,J=6.5 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.47 (t, J=7.8 Hz, 2H), 7.38 (m,2H), 7.26 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.46 (m, 2H), 2.21 (s, 3H).MS m/z 435.1 (M+Na).

Example 237: Synthesis of 2-(indolin-6-yl)-3-(phenylethynyl)benzoic acid

2-(indolin-6-yl)-3-(phenylethynyl)benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 7.84 (dd, J=7.8, 1.3Hz, 1H), 7.76 (dd, J=7.8, 1.3 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.44 (t,J=7.8 Hz, 1H), 7.39 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.24 (d, J=2.5 Hz,1H), 7.13 (dd, J=10.4, 6.7 Hz, 2H), 3.94 (d, J=7.7 Hz, 2H), 3.36 (s,2H). MS m/z 340.1 (M+H).

Example 238: Synthesis of3-((3-hydroxyphenyl)ethynyl)-2-(indolin-6-yl)benzoic acid

3-((3-hydroxyphenyl)ethynyl)-2-(indolin-6-yl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ7.99-7.83 (m, 1H), 7.85-7.69 (m, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51-7.39(m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.88 (d, J=7.5Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 4.23-3.73 (m, 2H), 3.40(s, 2H). MS m/z 356.1 (M+H).

Example 239: Synthesis of3-((6-aminopyridin-2-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((6-aminopyridin-2-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ8.65 (s, 1H), 7.74 (ddd, J=10.5, 7.7, 1.1 Hz, 2H), 7.63 (d, J=8.2 Hz,1H), 7.43 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.17-7.03 (m, 3H), 6.51 (s,1H), 6.20 (dd, J=16.1, 7.8 Hz, 1H), 4.57 (s, 2H). MS m/z 354.1 (M+H).

Example 240: Synthesis of3-((2-aminopyridin-4-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((2-aminopyridin-4-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ8.67 (s, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.78 (dd, J=7.8, 1.2 Hz, 1H),7.72-7.61 (m, 2H), 7.37 (dd, J=13.1, 5.2 Hz, 2H), 7.24-7.13 (m, 1H),7.07 (dd, J=8.2, 1.2 Hz, 1H), 6.58 (s, 1H), 6.27 (d, J=5.2 Hz, 1H), 5.79(s, 1H), 4.28 (s, 2H). MS m/z 354.1 (M+H).

Example 241: Synthesis of3-((3-hydroxyphenyl)ethynyl)-2-(5-methoxypyridin-3-yl)benzoic acid

3-((3-hydroxyphenyl)ethynyl)-2-(5-methoxypyridin-3-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ8.50 (d, J=30.3 Hz, 2H), 8.14 (dd, J=7.9, 1.1 Hz, 1H), 8.09 (s, 1H),7.89 (dd, J=7.8, 1.1 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.9 Hz,1H), 6.77 (dd, J=8.2, 1.6 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.57 (s, 1H),4.02 (s, 3H). MS m/z 346.3 (M+H).

Example 242: Synthesis of2-(benzo[d][1,3]dioxol-5-yl)-3-((3-hydroxyphenyl) ethynyl)benzoic acid

2-(benzo[d][1,3]dioxol-5-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.71 (ddd, J=10.2, 7.8, 1.4 Hz, 2H), 7.42 (t, J=7.8 Hz, 1H),7.14-7.04 (m, 1H), 6.87 (dd, J=9.1, 4.8 Hz, 2H), 6.82-6.78 (m, 1H),6.76-6.70 (m, 1H), 6.66 (ddd, J=3.9, 2.5, 1.4 Hz, 1H), 5.99 (s, 2H). MSm/z 359.4 (M+H).

Example 243: Synthesis of3-((3-hydroxyphenyl)ethynyl)-2-(pyrimidin-5-yl)benzoic acid

3-((3-hydroxyphenyl)ethynyl)-2-(pyrimidin-5-yl)benzoic acid was preparedby the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 9.19 (s,1H), 8.78 (s, 2H), 8.10 (dd, J=7.9, 1.3 Hz, 1H), 7.87 (dd, J=7.8, 1.3Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.9 Hz, 2H), 6.84-6.68 (m,1H), 6.63 (d, J=8.0 Hz, 1H), 6.57 (d, J=1.3 Hz, 1H). MS m/z 317.3 (M+H).

Example 244: Synthesis of4′-Amino-6-((3-hydroxyphenyl)ethynyl)-5′-methoxybiphenyl-2-carboxylicacid

4′-amino-6-((3-hydroxyphenyl)ethynyl)-5′-methoxybiphenyl-2-carboxylicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.81 (ddd, J=30.0, 7.8, 1.3 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H),7.35 (d, J=8.0 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.08 (t, J=7.9 Hz, 1H),7.00 (dd, J=8.0, 1.7 Hz, 1H), 6.74 (dd, J=8.2, 1.5 Hz, 1H), 6.60 (dd,J=13.2, 5.0 Hz, 2H), 3.88 (s, 3H). MS m/z 360.2 (M+H).

Example 245: Synthesis of3-(4-hydroxybut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid

3-(4-hydroxybut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CDCl₃) δ 8.54 (m,1H), 7.73-7.64 (m, 1H), 7.65-7.49 (m, 2H), 7.29 (dd, J=16.2, 8.4 Hz,2H), 7.18-7.05 (m, 1H), 7.01 (dd, J=8.1, 1.4 Hz, 1H), 6.54 (d, J=2.1 Hz,1H), 3.15 (t, J=6.4 Hz, 2H), 2.22 (t, J=6.5 Hz, 2H). MS m/z 306.1 (M+H).

Example 246: Synthesis of3-(3-amino-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid

3-(3-amino-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.70 (ddd, J=16.2, 7.8, 1.4 Hz, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.43 (dd,J=13.4, 5.7 Hz, 2H), 7.29 (d, J=3.2 Hz, 2H), 6.93 (dd, J=8.1, 1.6 Hz,1H), 6.49 (dd, J=3.2, 0.9 Hz, 1H), 3.56 (s, 6H). MS m/z 318.1 (M+H).

Example 247: Synthesis of3-(3-hydroxy-3-phenylprop-1-ynyl)-2-(1H-indol-6-yl)benzoic acid

3-(3-hydroxy-3-phenylprop-1-ynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.76-7.63 (m, 2H), 7.52 (t, J=7.2 Hz, 1H), 7.40 (dd, J=10.1, 5.4 Hz,2H), 7.36-7.30 (m, 1H), 7.29-7.21 (m, 1H), 7.14-6.98 (m, 1H), 7.02-6.82(m, 4H), 6.56-6.44 (m, 1H), 5.36 (s, 1H). MS m/z 368.3 (M+H).

Example 248: Synthesis of3-(3-hydroxy-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid

3-(3-hydroxy-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ10.48 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.62 (t, J=10.2 Hz, 1H),7.47-7.35 (m, 1H), 7.30-7.19 (m, 1H), 7.20-7.04 (m, 1H), 7.01 (d, J=1.7Hz, 1H), 6.82-6.69 (m, 1H), 6.49 (d, J=2.2 Hz, 1H), 2.98 (s, 6H). MS m/z342.1 (M+Na).

Example 249: Synthesis of3-((3-(hydroxymethyl)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-(hydroxymethyl)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ10.53 (s, 1H), 7.76-7.64 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.48-7.44 (m,1H), 7.44-7.36 (m, 1H), 7.28 (dt, J=3.0, 1.2 Hz, 1H), 7.25-7.19 (m, 1H),7.15 (t, J=7.4 Hz, 1H), 7.04 (dt, J=3.3, 1.6 Hz, 1H), 7.00-6.83 (m, 2H),6.57-6.42 (m, 1H), 4.77 (d, J=65.2 Hz, 2H). MS m/z 368.0 (M+H).

Example 250: Synthesis of6-(2-carboxy-6-(phenylethynyl)phenyl)-1H-indole-2-carboxylic acid

6-(2-carboxy-6-(phenylethynyl)phenyl)-1H-indole-2-carboxylic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.74 (ddd, J=7.8, 5.0, 1.4 Hz, 2H), 7.65 (dd, J=1.6, 0.8 Hz, 1H), 7.50(dt, J=8.6, 0.8 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.25 (m, 1H),7.25-7.13 (m, 4H), 7.04 (dt, J=8.2, 2.1 Hz, 2H). MS m/z 382.0 (M+H).

Example 251: Synthesis of2-(2-(ethoxycarbonyl)-1H-indol-6-yl)-3-(phenylethynyl)benzoic acid

2-(2-(ethoxycarbonyl)-1H-indol-6-yl)-3-(phenylethynyl)benzoic acid wasprepared by the same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ7.81-7.69 (m, 2H), 7.65 (d, J=0.9 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.42(dd, J=15.2, 7.4 Hz, 1H), 7.35-7.27 (m, 1H), 7.24-7.10 (m, 4H), 7.03(dd, J=8.0, 1.6 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).MS m/z 410.1 (M+H).

Example 252: Synthesis of3-((3-carbamoyl-5-methoxyphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-carbamoyl-5-methoxyphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acidwas prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.74 (ddd, J=7.8, 4.6, 1.4 Hz, 2H), 7.62 (d, J=8.2 Hz, 1H),7.45 (dd, J=9.9, 5.6 Hz, 2H), 7.27 (dd, J=3.6, 2.0 Hz, 2H), 7.22 (t,J=1.4 Hz, 1H), 7.05 (dd, J=8.1, 1.5 Hz, 1H), 6.51 (ddd, J=5.0, 2.8, 1.1Hz, 2H), 3.66 (s, 3H). MS m/z 411.2 (M+H).

Example 253: Synthesis of 2-(1H-indol-5-yl)-3-(phenylethynyl)benzoicacid

2-(1H-indol-5-yl)-3-(phenylethynyl)benzoic acid was prepared by the sameprocedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 7.71 (ddd, J=7.8,4.8, 1.4 Hz, 2H), 7.60 (dd, J=1.7, 0.7 Hz, 1H), 7.45-7.38 (m, 2H),7.30-7.25 (m, 1H), 7.23-7.13 (m, 4H), 7.06 (ddd, J=6.4, 3.8, 2.0 Hz,2H), 6.49 (dd, J=3.2, 0.9 Hz, 1H). MS m/z 338.2 (M+H).

Example 254: Synthesis of5-(2-carboxy-6-((3-hydroxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylicacid

5-(2-carboxy-6-((3-hydroxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.70 (dd, J=7.7, 1.4 Hz, 1H), 7.62 (dd, J=7.8, 1.4 Hz, 1H),7.57-7.51 (m, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.30 (dd, J=8.5, 1.7 Hz, 1H),7.20 (d, J=0.9 Hz, 1H), 7.00 (dd, J=11.5, 4.8 Hz, 1H), 6.67 (ddd, J=8.2,2.4, 1.2 Hz, 1H), 6.57-6.46 (m, 2H). MS m/z 398.0 (M+H).

Example 255: Synthesis of5-(2-carboxy-6-((4-methoxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylicacid

5-(2-carboxy-6-((4-methoxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.69-7.62 (m, 1H), 7.58 (ddd, J=4.7, 2.3, 1.1 Hz, 2H), 7.52(dt, J=8.5, 0.8 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.28 (dd, J=8.5, 1.7Hz, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04-6.90 (m, 2H), 6.78-6.69 (m, 2H),3.69 (s, 3H). MS m/z 412.2 (M+H).

Example 256: Synthesis of3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoicacid was prepared by the same procedure as example 119. ¹H NMR (300 MHz,CD₃OD) δ 7.71 (ddd, J=9.2, 8.1, 1.4 Hz, 2H), 7.59 (dd, J=11.1, 10.5 Hz,1H), 7.48-7.37 (m, 2H), 7.29 (t, J=9.2 Hz, 1H), 7.10-7.01 (m, 1H), 6.95(dd, J=11.1, 8.4 Hz, 1H), 6.74 (ddd, J=8.4, 4.4, 2.0 Hz, 1H), 6.50 (ddd,J=9.9, 5.6, 1.4 Hz, 2H), 4.31-4.10 (m, 1H), 4.00-3.77 (m, 2H), 3.55(ddd, J=17.7, 10.6, 6.7 Hz, 2H), 2.03-1.71 (m, 2H), 1.61 (ddd, J=21.1,7.6, 3.7 Hz, 2H). MS m/z 456.2 (M+H).

Example 257: Synthesis of5′-acetamido-6-(phenylethynyl)biphenyl-2-carboxylic acid

5′-acetamido-6-(phenylethynyl)biphenyl-2-carboxylic acid was prepared bythe same procedure as example 119. ¹H NMR (300 MHz, CD₃OD) δ 7.81 (dd,J=7.8, 1.3 Hz, 1H), 7.78-7.66 (m, 2H), 7.54 (t, J=1.9 Hz, 1H), 7.47 (t,J=7.8 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.30-7.21 (m, 3H), 7.19-7.10 (m,2H), 7.08 (d, J=7.6 Hz, 1H), 2.11 (s, 3H). MS m/z 356.2 (M+H).

Example 258: Synthesis of3-[3-(5-amino-1H-1,3-benzodiazol-1-yl)prop-1-yn-1-yl]-2-phenylbenzoicacid trifluoroacetate salt

3-[3-(5-amino-1H-1,3-benzodiazol-1-yl)prop-1-yn-1-yl]-2-phenylbenzoicacid trifluoroacetate salt was prepared by the same procedure as example157. ¹H NMR (300 MHz, DMSO) δ=8.72 (br. s., 1H), 7.71 (ddd, J=1.5, 7.8,13.0 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.25-7.10 (m, 6H), 6.71 (d, J=7.9Hz, 2H), 5.31 (s, 2H), MS (ES⁺)=367.94 (MH)⁺.

Example 259: Synthesis of2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt

2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt was prepared by the same procedure as example 174.¹H NMR (300 MHz, DMSO) δ=11.19 (s, 1H), 8.55 (br. s., 2H), 7.82 (dd,J=1.5, 7.6 Hz, 1H), 7.74 (dd, J=1.5, 7.6 Hz, 1H), 7.64-7.45 (m, 2H),7.44-7.36 (m, 2H), 7.17 (d, J=6.2 Hz, 2H), 7.03 (dd, J=1.8, 8.2 Hz, 1H),6.47 (ddd, J=0.9, 2.0, 3.0 Hz, 1H). MS (ES⁺)=339.00 (MH)⁺.

Example 260: Synthesis of2-(4-methylphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt

2-(4-methylphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt was prepared by the same procedure as example 174.¹H NMR (300 MHz, DMSO) δ=8.59 (d, J=5.6 Hz, 2H), 7.80 (ddd, J=1.2, 7.7,10.5 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.28-7.16 (m, 6H), 2.37 (s, 3H).MS (ES⁺)=314.00 (MH)⁺.

Example 261: Synthesis of 3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methylphenyl)benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methylphenyl)benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=9.62 (br. s., 1H), 7.81-7.62 (m, 2H), 7.52-7.40 (m, 1H), 7.30-7.16 (m,5H), 7.16-7.06 (m, 1H), 6.74 (ddd, J=0.9, 2.3, 8.2 Hz, 1H), 6.65-6.51(m, 2H), 2.36 (s, 3H). MS (ES)=328.11 (MH)⁺.

Example 262: Synthesis of3-{3-[(1H-1,3-benzodiazol-6-yl)amino]prop-1-yn-1-yl}-2-phenylbenzoicacid; trifluoroacetate salt

3-{3-[(1H-1,3-benzodiazol-6-yl)amino]prop-1-yn-1-yl}-2-phenylbenzoicacid; trifluoroacetate salt was prepared by the same procedure asexample 157. ¹H NMR (300 MHz, DMSO) δ=8.68 (br. s., 1H), 7.77-7.64 (m,2H), 7.51-7.41 (m, 1H), 7.32-7.08 (m, 7H), 6.79-6.62 (m, 2H), 5.30 (s,2H). MS (ES)=368.01 (MH)⁺.

Example 263: Synthesis of3-[2-(3-hydroxyphenyl)ethynyl]-2-(1-methyl-1H-indol-5-yl)benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1-methyl-1H-indol-5-yl)benzoic acidwas prepared by the same procedure as example 166. ¹H NMR (300 MHz,DMSO) δ=9.57 (br. s., 1H), 7.76-7.69 (m, 1H), 7.65 (dd, J=1.5, 7.6 Hz,1H), 7.56-7.49 (m, 1H), 7.49-7.40 (m, 2H), 7.34 (d, J=3.2 Hz, 1H),7.19-7.11 (m, 1H), 7.10-6.99 (m, 1H), 6.76-6.64 (m, 1H), 6.61-6.51 (m,2H), 6.48-6.42 (m, 1H), 3.87-3.77 (m, 3H). MS (ES)=368.08 (MH)⁺.

Example 264: Synthesis of3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)benzoicacid; trifluoroacetate salt

3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)benzoicacid; trifluoroacetate salt was prepared by the same procedure asexample 166. ¹H NMR (300 MHz, DMSO) δ=7.70-7.64 (m, 1H), 7.63-7.56 (m,1H), 7.44-7.32 (m, 1H), 7.14 (t, J=7.9 Hz, 1H), 6.80-6.63 (m, 5H), 4.25(dd, J=3.8, 5.0 Hz, 2H), 3.33-3.21 (m, 2H), 2.87 (s, 3H). MS(ES⁺)=386.09 (MH)⁺.

Example 265: Synthesis of 3-[2-(3-hydroxyphenyl)ethynyl]-2-(3-methanesulfonamidophenyl)benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(3-methanesulfonamidophenyl)benzoicacid was prepared by the same procedure as example 166. ¹H NMR (300 MHz,DMSO) δ=9.81 (s, 1H), 9.63 (br. s., 1H), 7.75 (qd, J=1.6, 7.8 Hz, 2H),7.55-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.25-7.18 (m, 1H), 7.16-7.01 (m,3H), 6.74 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 6.62-6.52 (m, 2H), 2.88 (s,3H). MS (ES⁺)=430.00 (M+Na)⁺.

Example 266: Synthesis of3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-6-yl)benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-6-yl)benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=11.15 (s, 1H), 9.57 (br. s., 1H), 7.79-7.71 (m, 1H), 7.69-7.60 (m,1H), 7.60-7.53 (m, 1H), 7.50-7.41 (m, 1H), 7.41-7.33 (m, 2H), 7.11-6.96(m, 2H), 6.76-6.63 (m, 2H), 6.60-6.50 (m, 2H), 6.49-6.42 (m, 1H). MS(ES⁺)=354.01 (MH)⁺.

Example 267: Synthesis of 2-(3-carbamoylphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid

2-(3-carbamoylphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=9.58 (br. s., 1H), 7.99 (s, 1H), 7.95-7.83 (m, 3H), 7.83-7.73 (m, 2H),7.57-7.42 (m, 3H), 7.39-7.29 (m, 1H), 7.13-7.01 (m, 1H), 6.73 (ddd,J=1.0, 2.4, 8.3 Hz, 1H), 6.59-6.48 (m, 2H). MS (ES⁺)=380.04 (M+Na)⁺.

Example 268: Synthesis of2-[1-(benzenesulfonyl)-1H-indol-3-yl]-3-[2-(3-hydroxyphenyl)ethynyl]benzoicacid

2-[1-(benzenesulfonyl)-1H-indol-3-yl]-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid was prepared by the same procedure as example 166. ¹H NMR(300 MHz, DMSO) δ=9.55 (br. s., 1H), 7.97-7.86 (m, 3H), 7.85-7.77 (m,3H), 7.61-7.46 (m, 2H), 7.42-7.29 (m, 3H), 7.26-7.18 (m, 2H), 6.92 (t,J=7.9 Hz, 1H), 6.68 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 6.29 (dd, J=1.5, 2.3Hz, 1H), 5.94 (td, J=1.2, 7.8 Hz, 1H). MS (ES⁺)=352.99 (M-140)⁺.

Example 269: Synthesis of 2-(3-hydroxyphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid

2-(3-hydroxyphenyl)-3-[2-(3-hydroxyphenyl) ethynyl]benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=9.63 (br. s., 1H), 9.42 (br. s., 1H), 7.69 (ddd, J=1.2, 7.8, 14.5 Hz,2H), 7.52-7.37 (m, 1H), 7.27-7.16 (m, 1H), 7.17-7.06 (m, 1H), 6.82-6.68(m, 4H), 6.68-6.54 (m, 2H), 3.95 (s, 1H). MS (ES⁺)=312.98 (MH−H₂O)⁺.

Example 270: Synthesis of2-(1H-indol-5-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt

2-(1H-indol-5-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt was prepared by the same procedure as example 174.¹H NMR (300 MHz, DMSO) δ=11.17 (s, 1H), 8.58-8.46 (m, 2H), 7.81 (dd,J=1.2, 7.9 Hz, 1H), 7.73 (dd, J=0.9, 7.9 Hz, 1H), 7.57-7.40 (m, 3H),7.38 (t, J=2.6 Hz, 1H), 7.17 (dd, J=1.8, 4.4 Hz, 2H), 7.11 (dd, J=1.6,8.4 Hz, 1H), 6.47 (t, J=2.2 Hz, 1H). MS (ES⁺)=339.07 (MH)⁺.

Example 271: Synthesis of2-(3-chloro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt

2-(3-chloro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt was prepared by the same procedure as example 174.¹H NMR (300 MHz, DMSO) δ=10.04 (br. s., 1H), 8.70-8.55 (m, 2H),7.89-7.78 (m, 2H), 7.65-7.48 (m, 1H), 7.29-7.20 (m, 2H), 6.83 (td,J=2.0, 12.5 Hz, 2H), 6.69 (dd, J=1.5, 2.3 Hz, 1H), 6.25-6.06 (m, 1H). MS(ES⁺)=350.00 (MH)⁺.

Example 272: Synthesis of2-(3-fluoro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt

2-(3-fluoro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt was prepared by the same procedure as example 174.¹H NMR (300 MHz, DMSO) δ=9.96 (br. s., 1H), 8.55 (d, J=5.9 Hz, 2H),7.88-7.67 (m, 2H), 7.56-7.41 (m, 1H), 7.22-7.08 (m, 2H), 6.61-6.45 (m,3H). MS (ES⁺)=334.04 (MH)⁺.

Example 273: Synthesis of2-(3,5-dimethoxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt

2-(3,5-dimethoxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid;trifluoroacetate salt was prepared by the same procedure as example 174.¹H NMR (300 MHz, DMSO) δ=8.61 (br. s., 2H), 7.80 (ddd, J=1.3, 7.7, 13.3Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.21 (d, J=5.9 Hz, 2H), 6.61-6.52 (m,1H), 6.49 (d, J=2.3 Hz, 2H), 3.73 (s, 6H). MS (ES⁺)=360.06 (MH)⁺.

Example 274: Synthesis of3-[3-(4-fluorophenyl)-3-hydroxyprop-1-yn-1-yl]-2-(3-hydroxyphenyl)benzoicacid

3-[3-(4-fluorophenyl)-3-hydroxyprop-1-yn-1-yl]-2-(3-hydroxyphenyl)benzoicacid was prepared by the same procedure as example 33. ¹H NMR (300 MHz,DMSO) δ=9.18 (br. s., 1H), 7.47-7.37 (m, 2H), 7.27-7.14 (m, 1H),6.98-6.73 (m, 5H), 6.55 (ddd, J=1.2, 2.3, 8.2 Hz, 1H), 6.44-6.34 (m,2H), 5.19-5.09 (m, 1H).

Example 275: Synthesis of3-[2-(3-hydroxyphenyl)ethynyl]-2-(2-phenoxyphenyl) benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(2-phenoxyphenyl) benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=9.63 (br. s., 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.72 (dd, J=1.5, 7.6Hz, 1H), 7.51-7.30 (m, 3H), 7.27-7.07 (m, 4H), 7.05-6.92 (m, 1H),6.92-6.80 (m, 3H), 6.74 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 6.62-6.49 (m,2H). MS (ES⁺)=429.19 (M+Na)⁺.

Example 276: Synthesis of3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-3-yl)benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-3-yl)benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=11.29 (s, 1H), 9.53 (s, 1H), 7.74 (dd, J=1.3, 7.8 Hz, 1H), 7.65 (dd,J=1.5, 7.9 Hz, 1H), 7.48-7.37 (m, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.16-6.91(m, 3H), 6.69 (ddd, J=0.9, 2.6, 8.2 Hz, 1H), 6.50-6.34 (m, 2H). MS(ES⁺)=354.08 (MH)⁺.

Example 277: Synthesis of 2-(3,5-dimethoxyphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid

2-(3,5-dimethoxyphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid wasprepared by the same procedure as example 166. ¹H NMR (300 MHz, DMSO)δ=9.63 (br. s., 1H), 7.78-7.62 (m, 2H), 7.54-7.40 (m, 1H), 7.13 (t,J=7.9 Hz, 1H), 6.81-6.67 (m, 1H), 6.68-6.56 (m, 2H), 6.56-6.49 (m, 1H),6.47 (d, J=2.3 Hz, 2H), 3.82 (s, 6H). MS (ES⁺)=375.08 (MH)⁺.

Example 278: Synthesis of2-amino-3-[2-(3-carbamoylphenyl)ethynyl]benzoic acid; trifluoroacetatesalt

2-amino-3-[2-(3-carbamoylphenyl)ethynyl]benzoic acid; trifluoroacetatesalt was prepared by the same procedure as example 78. ¹H NMR (300 MHz,DMSO) δ=8.24-8.06 (m, 2H), 8.05-7.75 (m, 3H), 7.68-7.46 (m, 3H),6.76-6.58 (m, 1H), 3.38 (s, 2H). MS (ES⁺)=281.07 (MH)⁺.

Example 279: Synthesis of 2-amino-3-[2-(3-carboxyphenyl)ethynyl]benzoicacid; trifluoroacetate salt

2-amino-3-[2-(3-carboxyphenyl)ethynyl]benzoic acid; trifluoroacetatesalt was prepared by the same procedure as example 78. ¹H NMR (300 MHz,DMSO) δ=13.13 (br. s., 1H), 8.18 (br. s., 1H), 7.94 (d, J=7.6 Hz, 1H),7.83 (dd, J=7.8, 15.1 Hz, 2H), 7.64-7.45 (m, 2H), 6.59 (t, J=7.6 Hz,1H). MS (ES⁺)=282.09 (MH)⁺.

Example 280: Synthesis of5-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole5-(3-Ethynyl-phenyl)-1H-tetrazole

The solution of 5-(3-Bromo-phenyl)-1H-tetrazole (2 g, 8.9 mmol) intriethylamine (20 mL) was degassed under N₂ for 10 min.Trimethylsilylacetylene (1 mL), bis(triphenylphosphine)palladium(II)dichloride (624 mg, 0.89 mmol) and copper iodide (339 mg, 1.78 mmol) wasadded and the reaction mixture was degassed under N₂ for 20 min and thenheated at 60° C. for 18 hours. After cooling to ambient temperature, thecrude mixture was filtered through celite and washed withdichloromethane. The filtrate was concentrated and purified by columnchromatography through a silica gel cartridge (80 g) eluting withmethanol/dichloromethane (10-20%) to give the intermediate as a whitesolid. To this intermediate in methanol (10 mL) was slowly added 2N NaOH(3.5 mL, 7 mmol). The reaction mixture was stirred at room temperaturefor 20 minutes and concentrated, diluted with water (10 mL) andacidified with 2N hydrochloric acid aqueous solution until pH=1. Theprecipitate was filtered and purified through preparative HPLC to give810 mg (59% for 2 steps) of the pure product as a white solid.

5-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-1H-indole. A mixture of5-(3-ethynyl-phenyl)-1H-tetrazole (34 mg, 0.2 mmol), 5-iodo-indole (97mg, 0.4 mmol), palladium tetrakis-triphenylphosphine (23 mg, 0.02 mmol)and copper iodide (7.6 mg, 0.04 mmol), potassium carbonate (55.3 mg, 0.4mmol) in 1,2-dimethoxyethane/water (1 mL/0.3 mL) was degassed with N₂for 5 minutes and then heated at 60° C. for 3 hours. After cooling toambient temperature, the crude mixture was filtered through celite andwashed with dichloromethane. The filtrate was concentrated and purifiedby preparative HPLC to give 15.4 mg (27%) of the pure product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ=10.71 (br. s., 1H), 8.15 (d, J=2.3 Hz,1H), 7.96 (td, J=1.5, 7.8 Hz, 1H), 7.78 (s, 1H), 7.71-7.52 (m, 3H),7.44-7.34 (m, 1H), 7.31-7.25 (m, 2H), 6.48 (d, J=3.1 Hz, 1H). MS (ESI)m/z 285.0 (M)⁺.

Example 281: Synthesis of3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-pyrrolo[2,3-b]pyridine

3-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-1H-pyrrolo[2,3-b]pyridine wasprepared by the same procedure as example 280. ¹H NMR (300 MHz, DMSO)δ=12.23 (br. s., 1H), 8.33 (dd, J=1.5, 4.7 Hz, 1H), 8.20 (s, 1H), 8.13(dd, J=1.6, 7.8 Hz, 1H), 8.04-7.95 (m, 2H), 7.78-7.73 (m, 1H), 7.70-7.61(m, 1H), 7.22 (dd, J=4.7, 7.9 Hz, 1H). MS (ESI) m/z 287.1 (M+1)⁺.

Example 282: Synthesis of6-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole

6-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-1H-indole was prepared by thesame procedure as example 280. ¹H NMR (300 MHz, DMSO) δ=11.33 (br. s.,1H), 8.19 (d, J=2.5 Hz, 1H), 8.19 (s, 1H), 8.06-8.03 (m, 1H), 7.75 (td,J=5.0 Hz, 8.1 Hz, 1H), 7.67-7.55 (m, 3H), 7.49-7.46 (m, 1H), 7.19 (dd,J=1.3, 8.1 Hz, 1H), 6.50-6.47 (m, 1H); MS (ESI) m/z 285.1 (M)⁺.

Example 283: Synthesis of1-benzenesulfonyl-3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole

1-Benzenesulfonyl-3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole wasprepared by the same procedure as example 280. MS (ESI) m/z 426.0(M+1)⁺.

Example 284: Synthesis of3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole

3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole.1-Benzenesulfonyl-3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole, (30mg, 0.07 mmol) was dissolved in tetrahydrofuran/methanol (1 mL/0.2 mL)and added sodium hydroxide solution (2 N in water, 0.1 mL, 0.2 mmol) andthe solution was stirred at 60° C. for 18 hours. 1 N hydrochloric acidaqueous solution was added dropwise until pH=1 and the reaction mixturewas purified through preparative HPLC to give 17 mg (84%) of the pureproduct as a white solid. ¹H NMR (300 MHz, DMSO) δ=11.63 (br. s., 1H),8.18 (s, 1H), 8.03-8.01 (m, 1H), 7.83 (d, J=2.6 Hz, 1H), 7.76-7.61 (m,3H), 7.50-7.45 (m, 1H), 7.24-7.13 (m, 2H). MS (ESI) m/z 286.0 (M+1)⁺.

Example 285: Synthesis of{2-[3-(1H-tetrazol-5-yl)-phenylethynyl]-phenyl}-methanol

{2-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-phenyl}-methanol was prepared bythe same procedure as example 280. ¹H NMR (300 MHz, CD₃OD) δ=8.21 (br.s., 1H), 8.04 (d, J=7.0 Hz, 1H), 7.77-7.69 (m, 1H), 7.65-7.51 (m, 3H),7.42 (t, J=7.3 Hz, 1H), 7.35-7.27 (m, 1H), 4.92-4.84 (m, 2H). MS (ESI)m/z 300.0 (M+Na)⁺.

Example 286: Synthesis of3-[3-(morpholine-4-carbonyl)-phenylethynyl]-benzoic acid

3-[3-(Morpholine-4-carbonyl)-phenylethynyl]-benzoic acid. A mixture of3-(3-carbamoyl-5-methoxy-phenylethynyl)-benzoic acid (40 mg, 0.14 mmol),morpholine (0.1 mL), HATU (70 mg, 0.18 mmol) and triethylamine (0.1mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 24hours. The reaction mixture was concentrated and purified throughpreparative HPLC to give the ester intermediate. To this intermediate intetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxidesolution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirredat room temperature for 18 hours. 1 N hydrochloric acid aqueous solutionwas added dropwise until pH=1 and the reaction mixture was purifiedthrough preparative HPLC to give 8 mg (17% for 2 steps) of the pureproduct as a white solid. 18 mg (22% for 2 steps) of the pure product asa white solid. ¹H NMR (300 MHz, CD₃OD) δ=8.15 (s, 1H), 8.02 (d, J=7.6Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.68-7.60 (m, 2H), 7.55-7.42 (m, 3H),3.80-3.60 (m, 6H), 3.55-3.42 (m, 2H). MS (ESI) m/z 336.1 (M+1)⁺.

Example 287: Synthesis of 3-(3-methylcarbamoyl-phenylethynyl)-benzoicacid

3-(3-Methylcarbamoyl-phenylethynyl)-benzoic acid was prepared by thesame procedure as example 286. ¹H NMR (300 MHz, CD₃OD) δ=8.15 (t, J=1.6Hz, 1H), 8.05-7.99 (m, 2H), 7.82-7.79 (m, 1H), 7.76-7.69 (m, 2H),7.53-7.49 (m, 2H), 2.93 (s, 3H). MS (ESI) m/z 280.1 (M+1)⁺.

Example 288: Synthesis of 3-(3-dimethylcarbamoyl-phenylethynyl)-benzoicacid

3-(3-Dimethylcarbamoyl-phenylethynyl)-benzoic acid was prepared by thesame procedure as example 286. ¹H NMR (300 MHz, CD₃OD) δ=8.15 (t, J=1.3Hz, 1H), 8.02 (td, J=1.5, 7.9 Hz, 1H), 7.75 (td, J=1.4, 7.8 Hz, 1H),7.66-7.59 (m, 2H), 7.54-7.41 (m, 3H), 3.11 (s, 3H), 3.01 (s, 3H). MS(ESI) m/z 294.1 (M+1)⁺.

Example 289: Synthesis of3-[3-(4-methyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid

3-[3-(4-Methyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid wasprepared by the same procedure as example 286. ¹H NMR (300 MHz, CD₃OD) δ=8.14 (d, J=2.3 Hz, 1H), 8.02 (td, J=1.5, 7.9 Hz, 1H), 7.76-7.66 (m,3H), 7.56-7.47 (m, 3H), 3.95-3.72 (m, 2H), 3.70-3.12 (m, 6H), 2.94 (s,3H). MS (ESI) m/z 349.1 (M+1)⁺.

Example 290: Synthesis of3-[3-(4-phenyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid

3-[3-(4-Phenyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid wasprepared by the same procedure as example 286. ¹H NMR (300 MHz, CD₃OD) δ=8.15 (t, J=1.6 Hz, 1H), 8.02 (td, J=1.3, 7.9 Hz, 1H), 7.75 (td, J=1.5,7.6 Hz, 1H), 7.69-7.61 (m, 2H), 7.54-7.44 (m, 3H), 7.28-7.19 (m, 2H),7.01-6.95 (m, 2H), 6.90-6.81 (m, 1H), 3.91 (br. s., 2H), 3.69-3.53 (m,2H), 3.30-3.10 (m, 4H). MS (ESI) m/z 411.2 (M+1)⁺.

Example 291: Synthesis of 2-indol-1-yl-3-pyridin-4-ylethynyl-benzoicacid

2-Indol-1-yl-3-pyridin-4-ylethynyl-benzoic acid. A mixture of2-bromo-3-pyridin-4-ylethynyl-benzoic acid methyl ester (50 mg, 0.16mmol), indole (28 mg, 0.237 mmol), potassium phosphate (70 mg, 0.332mmol), copper iodide (3 mg, 0.016 mmol) andN,N′-dimethyl-cyclohexane-1,2-diamine (10 mg, 0.063 mmol) in toluene(1.5 mL) was degassed under N₂ for 10 minutes and then heated at 110° C.for 18 hours. After cooling to room temperature, the reaction mixturewas filtered through celite washing with ethyl acetate (5 mL). Thefiltrate was concentrated and purified using reversed phase HPLC toprovide the desired product as a white solid. ¹H NMR (300 MHz, CD₃OD)δ=8.57 (d, J=6.2 Hz, 2H), 8.13 (dd, J=1.5, 7.9 Hz, 1H), 7.99 (d, J=7.4Hz, 1H), 7.75-7.64 (m, 2H), 7.33 (d, J=3.5 Hz, 1H), 7.19-7.09 (m, 4H),7.05-6.99 (m, 1H), 6.71 (d, J=3.3 Hz, 1H). MS (ESI) m/z 339.1 (M+1)⁺.

Example 292: Synthesis of 2-imidazol-1-yl-3-pyridin-4-ylethynyl-benzoicacid

2-Imidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid. A mixture of2-bromo-3-pyridin-4-ylethynyl-benzoic acid methyl ester (50 mg, 0.16mmol), imidazole (50 mg, 0.74 mmol), copper iodide (60 mg, 0.32 mmol),cesium carbonate (82 mg, 0.25 mmol) in dimethylformamide (1.5 mL) wasdegassed under N₂ for 10 minutes and then heated at 120° C. for 18hours. After cooling to room temperature, the reaction mixture wasfiltered through celite washing with ethyl acetate (5 mL). The filtratewas concentrated and purified using reversed phase HPLC to provide thedesired product as a white solid. ¹H NMR (300 MHz, CD₃OD) δ=9.40 (br.s., 1H), 8.38 (dd, J=1.5, 7.9 Hz, 1H), 8.14 (dd, J=1.3, 7.8 Hz, 1H),7.96-7.78 (m, 5H), 7.74-7.64 (m, 2H). MS (ESI) m/z 290.1 (M+1)⁺.

Example 293: Synthesis of3-pyridin-4-ylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid

3-Pyridin-4-ylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid was prepared bythe same procedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=8.83 (s,1H), 8.52 (d, J=3.8 Hz, 2H), 8.23 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.90(d, J=7.6 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.29 (d, J=5.6 Hz, 2H). MS(ESI) m/z 291.12 (M+1)⁺.

Example 294: Synthesis of 2-imidazol-1-yl-3-phenylethynyl-benzoic acid

2-Imidazol-1-yl-3-phenylethynyl-benzoic acid was prepared by the sameprocedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=8.02 (s, 1H),7.97-7.68 (m, 4H), 7.64-7.58 (m, 1H), 7.34-7.22 (m, 5H). MS (ESI) m/z289.1 (M+1)⁺.

Example 295: Synthesis of 3-phenylethynyl-2-pyrazol-1-yl-benzoic acid

-Phenylethynyl-2-pyrazol-1-yl-benzoic acid prepared by the sameprocedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=7.97-7.69 (m, 4H),7.63-7.56 (m, 1H), 7.37-7.25 (m, 5H), 6.57 (br. s., 1H). MS (ESI) m/z289.1 (M+1)⁺.

Example 296: Synthesis of 3-phenylethynyl-2-[1,2,4]triazol-1-yl-benzoicacid

3-Phenylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid prepared by the sameprocedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=8.84 (br. s., 1H),8.23 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.69 (t,J=7.5 Hz, 1H), 7.40-7.23 (m, 5H). MS (ESI) m/z 290.1 (M+1)⁺.

Example 297: Synthesis of 2-benzoimidazol-1-yl-3-phenylethynyl-benzoicacid

2-Benzoimidazol-1-yl-3-phenylethynyl-benzoic acid prepared by the sameprocedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=8.32 (d, J=7.6 Hz,1H), 8.15-7.95 (m, 1H), 7.95-7.80 (m, 1H), 7.71-7.52 (m, 2H), 7.48 (br.s., 1H), 7.33-7.14 (m, 5H), 6.85 (d, J=7.3 Hz, 2H). MS (ESI) m/z 339.1(M+1)⁺.

Example 298: Synthesis of 2-indazol-1-yl-3-phenylethynyl-benzoic acid

2-Indazol-1-yl-3-phenylethynyl-benzoic acid prepared by the sameprocedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=8.27 (d, J=0.9 Hz,1H), 8.03 (dd, J=1.6, 7.8 Hz, 1H), 7.93-7.85 (m, 2H), 7.67 (t, J=7.8 Hz,1H), 7.45-7.37 (m, 1H), 7.31-7.10 (m, 5H), 6.78-6.73 (m, 2H). MS (ESI)m/z 339.1 (M+1)⁺.

Example 299: Synthesis of 2-indol-1-yl-3-phenylethynyl-benzoic acid

2-Indol-1-yl-3-phenylethynyl-benzoic acid prepared by the same procedureas example 293. ¹H NMR (300 MHz, CD₃OD) δ=7.97-7.92 (m, 1H), 7.87-7.83(m, 1H), 7.66-7.57 (m, 2H), 7.30-6.97 (m, 7H), 6.88-6.82 (m, 2H), 6.67(d, J=3.2 Hz, 1H). MS (ESI) m/z 338.0 (M+1)⁺.

Example 300: Synthesis of2-benzoimidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid

2-Benzoimidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid was prepared bythe same procedure as example 293. ¹H NMR (300 MHz, CD₃OD) δ=8.55 (d,J=6.3 Hz, 2H), 8.30 (d, J=7.4 Hz, 1H), 8.15-7.95 (m, 1H), 7.93-7.79 (m,1H), 7.72-7.51 (m, 2H), 7.44 (br. s., 1H), 7.25 (d, J=6.1 Hz, 2H), 6.88(d, J=7.3 Hz, 2H). MS (ESI) m/z 340.1 (M+1)⁺.

Formulations

The present invention also relates to compositions or formulations whichcomprise the EBNA1 inhibitors according to the present invention. Ingeneral, the compositions of the present invention comprise an effectiveamount of one or more EBNA1 inhibitors and salts thereof according tothe present invention which are effective and one or more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,Pa. (1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions.

Compounds of the present teachings can be administered orally,intravenously (both bolus and infusion), intraperitoneally,subcutaneously, intramuscular, or parenterally, neat or in combinationwith conventional pharmaceutical carriers. Applicable solid carriers caninclude one or more substances which can also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents, orencapsulating materials. The compounds can be formulated in conventionalmanner, for example, in a manner similar to that used for known EBNA1inhibitors. Oral formulations containing a compound disclosed herein cancomprise any conventionally used oral form, including tablets, capsules,buccal forms, troches, lozenges and oral liquids, suspensions orsolutions. In powders, the carrier can be a finely divided solid, whichis an admixture with a finely divided compound. In tablets, a compounddisclosed herein can be mixed with a carrier having the necessarycompression properties in suitable proportions and compacted in theshape and size desired. The powders and tablets can contain up to 99% ofthe compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intravenous,intramuscular, intraperitoneal or subcutaneous injection. Sterilesolutions can also be administered intravenously. Compositions for oraladministration can be in either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials, ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited to,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample, isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitably mixed with a surfactant such ashydroxyl-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

Parenteral injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Additionally, oneapproach for parenteral administration employs the implantation of aslow-release or sustained-released systems, which assures that aconstant level of dosage is maintained, according to U.S. Pat. No.3,710,795, incorporated herein by reference.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame seed oil, benzyl alcohol, sodiumchloride, tragacanth gum, or various buffers. Other adjuvants and modesof administration are well and widely known in the pharmaceutical art.The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e.propylene glycol), or micellar solubilization (i.e., Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3 butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose and blan fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables. Aqueoussolutions suitable for intravenous injection (bolus or infusion) arepreferably buffered and the liquid diluent first rendered isotonic.Aqueous solutions suitable for intravenous injection (bolus or infusion)are preferably sterile as prepared by standard pharmaceutical techniqueswell known to those skilled in the art. Pharmaceutical compositions arepreferably preserved against the contaminating action of microorganismssuch as fungi and bacteria by standard pharmaceutical techniques wellknown to those skilled in the art.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can be sterile and itsviscosity permits it to flow through a syringe. The form preferably isstable under the conditions of manufacture and storage and can bepreserved against the contaminating action of microorganisms such asbacteria and fungi. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (e.g., glycerol,propylene glycol and liquid polyethylene glycol), suitable mixturesthereof, and vegetable oils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more EBNA1inhibitors according to the present invention and one or moreexcipients; from about 0.01 mg to about 100 mg of one or more EBNA1inhibitors according to the present invention and one or moreexcipients; and from about 0.1 mg to about 10 mg of one or more EBNA1inhibitors according to the present invention; and one or moreexcipients. Oral dosages of the present invention, when used for theindicated effects, will range between about 0.05 to 1000 mg/day orally.The compositions are preferably provided in the form of scored tabletscontaining 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0,500.0 and 1000.0 mg of active ingredient. Infused dosages, intranasaldosages and transdermal dosages will range between 0.05 to 1000 mg/day.Subcutaneous, intravenous (bolus or infusion) and intraperitonealdosages will range between 0.05 to 1000 mg/day. Effective plasma levelsof the compounds of the present invention range from 0.002 mg/mL to 50mg/mL. Compounds of the present invention may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily.

PROCEDURES

The following procedures can be utilized in evaluating and selectingcompounds as EBNA1 inhibitors.

Inhibition of 5′-biotin-oPL4624 binding to His-EBNA1 using Alpha Screentechnology: Assays were performed using the DNA binding domain of EBNA1(amino acids 459-607), which was His-tagged (His-EBNA1) and theself-complementary biotinylated (bt) oligonucleotide with the sequence5′-bt-GGGTAGCATATGCTATCTAGATAGCAT-ATGCTACCC-3′ (bt-oPL4624). The proteinwas expressed in E. coli and purified according to Barwell, et al.(Barwell J A, Bochkarev A, Pfuetzner R A, Tong H, Yang D S, Frappier L,Edwards A M. (1995) Overexpression, purification, and crystallization ofthe DNA binding and dimerization domains of the Epstein-Barr virusnuclear antigen 1. J Biol Chem. 270: 20556-9.). The bt-oPL4624oligonucleotide was purchased from Integrated DNA Technologies, Inc(IDT). AlphaScreen donor, acceptor beads and white, opaque 384-wellassay plates were purchased from PerkinElmer, Inc.

Assays contained 15 nM His-EBNA1, 0.2 nM bt-oPL4624, 5 μg/mL AlphaScreenstreptavidin donor beads and nickel chelate acceptor beads, and a seriesof concentrations of test compound ranging from 3.2 nM to 100 μM in atotal volume of 40 μL assay buffer (25 mM Tris, pH 7.2, 160 mM NaCl, 1mM MgCl₂). His-EBNA1 (30 nM) and bt-oPL4624 (0.4 nM) were preincubatedwith 10 μg/mL nickel chelate AlphaScreen acceptor bead, or 10 μg/mLstreptavidin AlphaScreen donor bead, respectively, for 30 minutes atroom temperature in assay buffer. Twenty microliters ofHis-EBNA1/acceptor bead mix and bt-oPL4624/donor bead mix weretransferred to assay plates containing 0.4 μL of 1:3 serial dilutions oftest compounds previously prepared in DMSO at concentrations rangingfrom 0.32 μM to 10 mM. Nonspecific binding was determined with 5 μg/mLAlphaScreen acceptor bead in the absence of His-EBNA1. After 2 hrincubation at room temperature, the AlphaScreen signal was measured onthe Envision plate reader (PerkinElmer, Inc.) at 680 nm excitation and570 nm emission. Inhibition values at each concentration of testcompound were determined by setting 100% equal to raw data values in theabsence of EBNA1 and 0% equal to the raw data values in the presence ofEBNA1. Nonlinear regression fits of the inhibition values to a one-sitedose-response equation were performed using GraphPad Prism. Results fromscreening of representative compounds of the disclosure are described intable 6.

TABLE 6 Inhibition of 5′-biotin-oPL4624 binding to His-EBNA1 ofrepresentative compounds of the disclosure using Alpha Screentechnology: Alpha Screen Entry Compound Activity  13-{2-[3-(methylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1- +++ yl)benzoicacid  2 3-[2-(1H-indol-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 3 3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1- ++++yl)benzoic acid  42-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid ++++  53-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++  63-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1- ++ yl)benzoicacid  7 3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoicacid ++  8 3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid+++  9 3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-++++ pyrrol-1-yl)benzoic acid 103-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2- +++(1H-pyrrol-1-yl)benzoic acid 113-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(1H-pyrrol-1- ++++yl)benzoic acid 123-(2-{imidazo[1,2-a]pyridin-3-yl}ethynyl)-2-(1H-pyrrol-1- ++++yl)benzoic acid 133-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1- ++ yl)benzoicacid 14 2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5- +++yl}ethynyl)benzoic acid 153-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid++++ 16 3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoicacid ++++ 173-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++18 3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 193-{2-[2-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1- ++++ yl)benzoicacid 20 3-{2-[4-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1- ++++yl)benzoic acid 21 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(4- ++++methylphenyl)ethynyl]benzoic acid 222-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(3- ++++hydroxyphenyl)ethynyl]benzoic acid 233-[2-(2,3-dihydro-1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1- ++++ yl)benzoicacid 24 3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]-2-(1H-pyrrol-1- +++yl)benzoic acid 253-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethynyl]-2-(1H-pyrrol-1- ++yl)benzoic acid 263-[2-(1-methyl-1H-imidazol-5-yl)ethynyl]-2-(1H-pyrrol-1- ++ yl)benzoicacid 27 3-[2-(1-methyl-1H-imidazol-2-yl)ethynyl]-2-(1H-pyrrol-1- ++yl)benzoic acid 282-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-5-yl)ethynyl]benzoic acid ++ 292-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid ++++ 302-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-6- +++yl}ethynyl)benzoic acid 313-{2-[3-(2-hydroxypropan-2-yl)phenyl]ethynyl}-2-(1H-pyrrol-1- +++yl)benzoic acid 323-(3-hydroxy-4-methylpent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid +++33 3-(3-hydroxy-3-phenylprop-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid++++ 34 2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3- ++++yl}ethynyl)benzoic acid 353-[2-(1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 362-(1H-pyrrol-1-yl)-3-(2-{[1,2,4]triazolo[1,5-a]pyridin-7- ++++yl}ethynyl)benzoic acid 37 3-{2-[3-(dimethylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1- ++++ yl)benzoic acid38 3-[2-(3-fluoro-5-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1- ++++yl)benzoic acid 393-{2-[3-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1- ++++ yl)benzoicacid 40 3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoicacid ++ 413-[2-(1H-1,3-benzodiazol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid+++ 42 3-[2-(1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++43 3-[2-(1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 443-[2-(4-methylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 453-[2-(3,5-difluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++ 463-{2-[3-(difluoromethoxy)phenyl]ethynyl}-2-(1H-pyrrol-1- +++ yl)benzoicacid 47 3-ethynyl-2-(1H-pyrrol-1-yl)benzoic acid ++ 483-(3-amino-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid + 493-(3,3-dimethylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid +++ 502-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid ++++ 515-[2-(4-fluorophenyl)ethynyl]-4-(1H-pyrrol-1-yl)pyridine-3- +++carboxylic acid 525-(2-phenylethynyl)-4-(1H-pyrrol-1-yl)pyridine-3-carboxylic acid ++ 533-[2-(1-aminocyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid; ++++trifluoroacetic acid 543-[2-(1-hydroxycyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++ 553-(4-ethyl-3-hydroxyoct-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid ++++56 3-(2-{imidazo[1,2-a]pyrazin-6-yl}ethynyl)-2-(1H-pyrrol-1- ++++yl)benzoic acid 573-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 585-chloro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++59 5-chloro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid ++ 605-fluoro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +61 5-fluoro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid ++ 623-(2-cyclopropylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid ++++ 633-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid ++++64 3-[3-(dimethylamino)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid +65 3-(4-phenylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid ++++ 663-(5-hydroxypent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid ++++ 673-[2-(4-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++ 683-[2-(pyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++++ 693-[2-(pyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid ++ 703-[2-(3-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++ 713-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid +++ 723-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid ++++ 733-{3-[benzyl(methyl)amino]prop-1-yn-1-yl}-2-(1H-pyrrol-1- ++++yl)benzoic acid 743-[3-(1H-imidazol-1-yl)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid++++ 75 3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid ++ 763-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid ++ 773-[2-(1H-indol-5-yl)ethynyl]benzoic acid ++++ 782-amino-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid ++++ 792-amino-3-[2-(1H-indol-4-yl)ethynyl]benzoic acid ++++ 802-amino-3-[2-(1H-indol-6-yl)ethynyl]benzoic acid ++++ 812-amino-3-[2-(1H-indol-5-yl)ethynyl]benzoic acid ++++ 822-amino-3-{2-[3-(hydroxymethyl)phenyl]ethynyl}benzoic acid +++ 832-amino-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid +++ 842-amino-3-(2-phenylethynyl)benzoic acid ++ 852-fluoro-3-(2-phenylethynyl)benzoic acid +++ 862-fluoro-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid ++ 872-fluoro-3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)benzoic acid ++++ 882-fluoro-3-{2[2-(hydroxymethyl)phenyl]ethynyl}benzoic acid +++ 892-fluoro-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid +++ 903-[2-(pyridin-2-yl)ethynyl]benzoic acid + 913-[2-(pyridin-3-yl)ethynyl]benzoic acid +++ 923-(2-phenylethynyl)benzoic acid ++ 93 3-[2-(pyridin-4-yl)ethynyl]benzoicacid +++ 94 3-[2-(4-methoxyphenyl)ethynyl]benzoic acid + 952-{4-[(dimethylamino)methyl]phenyl}-3-(2-phenylethynyl)benzoic +++ acidtrifluoroacetic acid salt 963-(2-phenylethynyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid +++trifluoroacetic acid salt 97 3-(2-phenylethynyl)-2-(pyridin-4-yl)benzoicacid trifluoroacetic ++ acid salt 982-(4-methanesulfonylphenyl)-3-(2-phenylethynyl)benzoic acid ++ 993-(2-phenylethynyl)-2-(1H-pyrazol-4-yl)benzoic acid +++ 1003-(2-phenylethynyl)-2-(pyrimidin-5-yl)benzoic acid + 1012-(1-methyl-1H-pyrazol-4-yl)-3-(2-phenylethynyl)benzoic acid +++ 1023-(2-phenylethynyl)-2-(2-phenylpyrrolidin-1-yl)benzoic acid +++ 1032-[3-(dimethylamino)pyrrolidin-1-yl]-3-(2-phenylethynyl)benzoic acid ++104 1-[2-carboxy-6-(2-phenylethynyl)phenyl]pyrrolidine-3-carboxylic acid++ 105 2-[(3S)-3-hydroxypyrrolidin-1-yl]-3-(2-phenylethynyl)benzoicacid + 106 3-(2-phenylethynyl)-2-(pyrrolidin-1-yl)benzoic acid ++ 1073-(2-phenylethynyl)-2-(piperazin-1-yl)benzoic acid ++ 1082-(benzylamino)-3-(2-phenylethynyl)benzoic acid ++ 1092-(4-phenyl-1H-1,2,3-triazol-1-yl)-3-(2-phenylethynyl)benzoic acid ++110 2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-3-(2- ++phenylethynyl)benzoic acid 1113-(2-phenylethynyl)-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1- ++yl]benzoic acid 112 2-[4-(3-hydroxypropyl)-1H-1,2,3-triazol-1-yl]-3-(2-++ phenylethynyl)benzoic acid 113N-(dimethylsulfamoyl)-3-(2-phenylethynyl)-2-(1H-pyrrol-1- +++yl)benzamide 114N-(dimethylsulfamoyl)-3-[2-(4-fluorophenyl)ethynyl]-2-(1H- +++pyrrol-1-yl)benzamide 115N-(morpholine-4-sulfonyl)-3-(2-phenylethynyl)-2-(1H-pyrrol-1- +yl)benzamide 116N-[(1,1-dioxo-4-thiomorpholin-4-yl)sulfonyl]-3-(2-phenylethynyl)- ++2-(1H-pyrrol-1-yl)benzamide 1173-[2-(4-fluorophenyl)ethynyl]-N-methanesulfonyl-2-(1H-pyrrol-1- ++yl)benzamide 1183-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)-N-sulfamoylbenzamide ++ 1192-(4-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid +++ 1202-(3-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid +++ 1212-(2-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid ++ 1223-(2-phenylethynyl)-2-(quinolin-3-yl)benzoic acid ++ 1232-cyclopropyl-3-(2-phenylethynyl)benzoic acid +++ 1242-phenyl-3-(2-phenylethynyl)benzoic acid ++ 1252-(4-methylphenyl)-3-(2-phenylethynyl)benzoic acid +++ 1262-(6-methoxypyridin-3-yl)-3-(2-phenylethynyl)benzoic acid ++ 1272-[6-(dimethylamino)pyridin-3-yl]-3-(2-phenylethynyl)benzoic acid ++ 1282-[3-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid ++ 1292-(1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid ++++ 1302-[4-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid ++ 1312-(1-benzofuran-5-yl)-3-(2-phenylethynyl)benzoic acid ++ 1322-(1-benzothiophen-5-yl)-3-(2-phenylethynyl)benzoic acid ++ 1332-(1-methyl-1H-indol-5-yl)-3-(2-phenylethynyl)benzoic acid +++ 1342-(3-methanesulfonamidophenyl)-3-(2-phenylethynyl)benzoic acid +++ 1352-(naphthalen-2-yl)-3-(2-phenylethynyl)benzoic acid +++ 1362-(1-methyl-1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid +++ 1372-{2-[(2-hydroxyethyl)sulfamoyl]phenyl}-3-(2- ++ phenylethynyl)benzoicacid 138 2-[4-(cyclopropylcarbamoyl)phenyl]-3-(2-phenylethynyl)benzoicacid ++ 139 2-(1-methyl-1H-indazol-6-yl)-3-(2-phenylethynyl)benzoic acid++ 140 3-[2-(3-hydroxyphenyl)ethynyl]-2-(quinolin-3-yl)benzoic acid +++141 3-(5-hydroxypent-1-yn-1-yl)-2-(quinolin-3-yl)benzoic acid ++ 1423-[2-(4-methoxyphenyl)ethynyl]-2-(quinolin-3-yl)benzoic acid ++ 1433-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)-2-(quinolin-3- +++ yl)benzoicacid 144 3-[(1E)-3-methoxyprop-1-en-1-yl]-2 -(1H-pyrrol-1-yl)benzoicacid +++ 145 3-[(E)-2-phenylethenyl]-2-(1H-pyrrol-1-yl)benzoic acid ++146 3-[(E)-2-(4-fluorophenyl)ethenyl]-2-(1H-pyrrol-1-yl)benzoic acid ++147 3-(2-phenylethyl)-2-(1H-pyrrol-1-yl)benzoic acid ++ 1483-(2-phenylethyl)-2-(pyrrolidin-1-yl)benzoic acid ++ 1493-[2-(4-fluorophenyl)ethyl]-2-(1H-pyrrol-1-yl)benzoic acid ++ 1502-(1H-1,3-benzodiazol-6-yl)-3-(2-phenylethynyl)benzoic acid ++ 1512-(quinolin-3-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid ++ 1523-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzene-1-sulfonamide +++ 153N-[3-(2-phenylethynyl)-2-(1H-pyrrol-1- ++ yl)benzenesulfonyl]acetamide154 2-(dimethyl-1,2-oxazol-4-yl)-3-(2-phenylethynyl)benzoic acid +++ 1552-(benzyloxy)-3-(2-phenylethynyl)benzoic acid ++ 1562-[3-(methoxycarbonyl)-1H-indol-6-yl]-3-(2- +++ phenylethynyl)benzoicacid 157 3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid ++ 1583-(3-{[3-(1H-imidazol-1-yl)propyl]amino}prop-1-yn-1-yl)-2- ++phenylbenzoic acid 1592-phenyl-3-[3-(4-phenylpiperazin-1-yl)prop-1-yn-1-yl]benzoic acid ++ 1602-phenyl-3-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]benzoic acid ++ 1613-(3-hydroxyprop-1-yn-1-yl)-2-phenylbenzoic acid + 1623-{2-[3-(aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid +++163 3-{2-[3-(3,5-difluorobenzenesulfonamidomethyl)phenyl]ethynyl}- +++2-(1H-pyrrol-1-yl)benzoic acid 164 3-{2-[4-(1,2-dimethyl-1H-imidazole-5-+++ sulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid 1653-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H- ++++pyrrol-1-yl)benzoic acid 1662-(3-methoxyphenyl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3- ++yl}ethynyl)benzoic acid 1672-(1-methyl-1H-indazol-6-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3- ++yl}ethynyl)benzoic acid 1682-(2-methyl-1,3-benzothiazol-5-yl)-3-(2-{1H-pyrrolo[2,3- ++b]pyridin-3-yl}ethynyl)benzoic acid 1692-(3-methoxyphenyl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid ++ 1702-(1-methyl-1H-indazol-6-yl)-3-[2-(1,3-thiazol-4- +++ yl)ethynyl]benzoicacid 1712-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid+++ 172 2-(pyridin-4-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid ++173 2-(2-methyl-1,3-benzothiazol-5-yl)-3-[2-(1,3-thiazol-4- ++yl)ethynyl]benzoic acid 1742-(1H-indol-3-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid +++ 1752-[4-(dimethylamino)phenyl]-3-[2-(pyridin-4-yl)ethynyl]benzoic acid ++176 2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-3-[2-(pyridin-4- ++yl)ethynyl]benzoic acid 177 2-phenyl-3-[2-(pyridin-4-yl)ethynyl]benzoicacid + 178 6-(3-carboxy-phenylethynyl)-1H-indole-4-carboxylic acid +++179 3-(4-carbamoyl-1H-indol-6-ylethynyl)-benzoic acid +++ 1803-(3-carbamoyl-phenylethynyl)-benzoic acid ++++ 1813-(1-benzenesulfonyl-1H-indol-3-ylethynyl)-benzoic acid ++ 1823-(1H-indol-3-ylethynyl)-benzoic acid ++ 1833-(3-carboxy-phenylethynyl)-benzoic acid methyl ester + 1843-(3-carbamoyl-5-methoxy-phenylethynyl)-benzoic acid ++ 1853′-hydroxy-4′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2- + carboxylicacid 186 5′-hydroxy-3′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2- ++carboxylic acid 187 2-(1H-pyrazol-3-yl)-3-pyridin-4-ylethynyl-benzoicacid ++ 188 2-(1H-pyrazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid + 1892-(3,5-dimethyl-isoxazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid ++ 1903-phenylethynyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzoic acid + 1912-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-methyl-but-1-ynyl)- ++benzoic acid 1922-(2,5-dimethyl-pyrrol-1-yl)-3-pyridin-4-ylethynyl-benzoic acid ++ 1933-(3-carbamoyl-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)- +++ benzoicacid 1943-(3-carboxy-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid++++ 195 2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxymethyl-phenylethynyl)-++ benzoic acid 1962-(2,5-dimethyl-pyrrol-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3- +++ylethynyl)-benzoic acid 1972-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-phenyl-prop-1-ynyl)- ++benzoic acid 1983-(3-acetylamino-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)- ++ benzoicacid 199 3-cyclopropylethynyl-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid+++ 200 2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-methoxy-phenylethynyl)-benzoicacid +++ 201 2-(1H-indazol-6-yl)-3-phenylethynyl-benzoic acid ++ 2022-benzo[1,3]dioxol-5-yl-3-phenylethynyl-benzoic acid ++ 2032-isoquinolin-6-yl-3-phenylethynyl-benzoic acid ++ 2042-benzofuran-2-yl-3-phenylethynyl-benzoic acid +++ 2053-phenylethynyl-2-quinolin-8-yl-benzoic acid ++ 2062-(2-amino-pyrimidin-5-yl)-3-phenylethynyl-benzoic acid + 2074′-dimethylaminomethyl-6-phenylethynyl-biphenyl-2-carboxylic acid + 2083-(4-amino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid +++ 2093-(4-carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid ++++ 2102-(1H-indol-6-yl)-3-(4-methoxy-phenylethynyl)-benzoic acid +++ 2113-(4-carbamoyl-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid +++ 2122-(1H-indol-6-yl)-3-[4-(piperazine-1-carbonyl)-phenylethynyl]- +++benzoic acid 2133-(4-acetylamino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid ++ 2142-(1H-indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]- ++++phenylethynyl}-benzoic acid 2152-(1H-indol-6-yl)-3-(4-methanesulfonylamino-phenylethynyl)- +++ benzoicacid 216 2-(1H-indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)- +++phenylethynyl]-benzoic acid 2172-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl) +++benzoic acid 218 2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoic acid+++ 219 2-(1-methyl-1H-pyrazol-4-yl)-3-(thiazol-4-ylethynyl) benzoicacid ++ 220 3-((3-hydroxyphenyl)ethynyl)-2-(1-methyl-1H-pyrazol-4- +++yl)benzoic acid 2212-(3-chloro-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid +++222 3-((3-hydroxyphenyl)ethynyl)-2-(1H-indazol-6-yl)benzoic acid +++ 2232-(3-(2-acetamidoethyl)-1H-indol-6-yl)-3((3- +++hydroxyphenyl)ethynyl)benzoic acid 2243-((3-(N,N-dimethylsulfamoyl)phenyl)ethynyl)-2-fluorobenzoic acid ++ 2252-(1H-indol-6-yl)-3((4-(tetrahydro-2H-pyran-4- ++++yloxy)phenyl)ethynyl)benzoic acid 2262-(1H-indol-6-yl)-3((4-morpholinophenyl)ethynyl)benzoic acid ++ 2273-((3-carbamoylphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid ++ 2283((4-Fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid +++ 2293((2,4-Difluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid +++ 2303-((3-Acetamidophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid ++++ 2312-(1H-indol-6-yl)-3((3-(nicotinamido)phenyl)ethynyl)benzoic acid +++ 2323-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H- ++++indol-6-yl)benzoic acid 2333-((3-aminophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid ++++ 2342-(1H-indol-6-yl)-3-((3- +++ (methylsulfonamido)phenyl)ethynyl)benzoicacid 235 2-(1H-indol-6-yl)-3-((3-(thiophene-2- ++++sulfonamido)phenyl)ethynyl)benzoic acid 2363-((3-acetamido-5-fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid++++ 237 2-(indolin-6-yl)-3-(phenylethynyl)benzoic acid ++ 2383-((3-hydroxyphenyl)ethynyl)-2-(indolin-6-yl)benzoic acid +++ 2393-((6-aminopyridin-2-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid +++ 2403-((2-aminopyridin-4-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid +++ 2413-((3-hydroxyphenyl)ethynyl)-2-(5-methoxypyridin-3-yl)benzoic acid ++242 2-(benzo[d][1,3]dioxol-5-yl)-3-((3-hydroxyphenyl)ethynyl)benzoicacid ++ 243 3-((3-hydroxyphenyl)ethynyl)-2-(pyrimidin-5-yl)benzoic acid++ 244 4′-Amino-6-((3-hydroxyphenyl)ethynyl)-5′-methoxybiphenyl-2- ++carboxylic acid 245 3-(4-hydroxybut-1-ynyl)-2-(1H-indol-6-yl) benzoicacid ++++ 246 3-(3-amino-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoicacid +++ 247 3-(3-hydroxy-3-phenylprop-1-ynyl)-2-(1H-indol-6-yl)benzoicacid ++++ 248 3-(3-hydroxy-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoicacid ++++ 2493-((3-(hydroxymethyl)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid +++250 6-(2-carboxy-6-(phenylethynyl)phenyl)-1H-indole-2-carboxylic acid+++ 251 2-(2-(ethoxycarbonyl)-1H-indol-6-yl)-3-(phenylethynyl)benzoicacid +++ 252 3-((3-carbamoyl-5-methoxyphenyl)ethynyl)-2-(1H-indol-6- +++yl)benzoic acid 253 2-(1H-indol-5-yl)-3-(phenylethynyl)benzoic acid +++254 5-(2-carboxy-6-((3-hydroxyphenyl)ethynyl)phenyl)-1H-indole-2- ++carboxylic acid 2555-(2-carboxy-6((4-methoxyphenyl)ethynyl)phenyl)-1H-indole-2- ++carboxylic acid 2563-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)-2- +++(1H-indol-6-yl)benzoic acid 2575′-acetamido-6-(phenylethynyl)biphenyl-2-carboxylic acid ++ 2583-[3-(5-amino-1H-1,3-benzodiazol-1-yl)prop-1-yn-1-yl]-2- +++phenylbenzoic acid trifluoroacetate salt 2592-(1H-indol-6-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; +++trifluoroacetate salt 2602-(4-methylphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; ++trifluoroacetate salt 2613-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methylphenyl)benzoic acid ++ 2623-{3-[(1H-1,3-benzodiazol-6-yl)amino]prop-1-yn-1-yl}-2- +++phenylbenzoic acid; trifluoroacetate salt 2633-[2-(3-hydroxyphenyl)ethynyl]-2-(1-methyl-1H-indol-5- +++ yl)benzoicacid 264 3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl-3,4-dihydro-2H-1,4-+++ benzoxazin-7-yl)benzoic acid; trifluoroacetate salt 2653-[2-(3-hydroxyphenyl)ethynyl]-2-(3-methanesulfonamidophenyl) ++ benzoicacid 266 3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-6-yl)benzoic acid++++ 267 2-(3-carbamoylphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoicacid ++ 268 2[1-(benzenesulfonyl)-1H-indol-3-yl]-3[2-(3- ++hydroxyphenyl)ethynyl]benzoic acid 2692-(3-hydroxyphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid ++ 2702-(1H-indol-5-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; ++trifluoroacetate salt 2712-(3-chloro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic +++acid; trifluoroacetate salt 2722-(3-fluoro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic ++ acid;trifluoroacetate salt 2732-(3,5-dimethoxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; ++trifluoroacetate salt 2743-[3-(4-fluorophenyl)-3-hydroxyprop-1-yn-1-yl]-2-(3- +++ hydroxyphenyl)benzoic acid 275 3-[2-(3-hydroxyphenyl)ethynyl]-2-(2-phenoxyphenyl)benzoic acid ++ 276 3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-3-yl)benzoic acid ++ 2772-(3,5-dimethoxyphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid ++278 2-amino-3-[2-(3-carbamoylphenyl)ethynyl]benzoic acid; ++trifluoroacetate salt 279 2-amino-3-[2-(3-carboxyphenyl)ethynyl]benzoicacid; ++ trifluoroacetate salt 2805-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole +++ 2813-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-pyrrolo[2,3-b]pyridine ++ 2826-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole +++ 2831-benzenesulfonyl-3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole ++++284 3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole ++++ 285{2-[3-(1H-tetrazol-5-yl)-phenylethynyl]-phenyl}-methanol ++ 2863-[3-(morpholine-4-carbonyl)-phenylethynyl]-benzoic acid ++ 2873-(3-methylcarbamoyl-phenylethynyl)-benzoic acid ++ 2883-(3-dimethylcarbamoyl-phenylethynyl)-benzoic acid + 2893-[3-(4-methyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid + 2903-[3-(4-phenyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid ++ 2912-indol-1-yl-3-pyridin-4-ylethynyl-benzoic acid ++ 2922-imidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid + 2933-pyridin-4-ylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid ++ 2942-imidazol-1-yl-3-phenylethynyl-benzoic acid ++ 2953-phenylethynyl-2-pyrazol-1-yl-benzoic acid + 2963-phenylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid ++ 2972-benzoimidazol-1-yl-3-phenylethynyl-benzoic acid ++ 2982-indazol-1-yl-3-phenylethynyl-benzoic acid ++ 2992-indol-1-yl-3-phenylethynyl-benzoic acid +++ 3002-benzoimidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid ++ Alpha ScreenActivity: IC50 < 1 uM = ++++; 1 uM < IC50 < 10 uM = +++; 10 uM < IC50 <100 uM = ++; 100 uM < IC50 < 1 mM = +.

Cell based luciferase assay of EBNA1 inhibition: In vivo inhibition ofEBNA1 was determined for compounds of the disclosure using a cell basedluciferase reporter assay. EBNA1 binding to the Family of Repeat (FR)region is essential for EBV latent infection and host-cell viability,thus providing a physiologically meaningful cell-based readout. Aderivative of EBNA1, which is functionally equivalent to full-lengthEBNA1 and lacks the GGA repeats (90-325), was cloned intop3×FLAG-Myc-CMV™-24 (Sigma-Aldrich Co., LLC) (N803). To make the assaymore sensitive by reducing the expression levels of EBNA1, the CMVpromoter was excised and the TK promoter inserted upstream of EBNA1. Toenhance the EBNA1-driven luciferase signal, the activation domain ofherpes virus VP16 (411-490) was fused to the C-terminus of EBNA1 usingSacII and BamHI restriction sites, resulting in the plasmidpTK-3×FLAG-Myc-EBNA1-VP16AD. Empty vector p3×FLAG-Myc-CMV-24 was used asa control. To create luciferase reporter plasmid, the FR region, a locusof 21 contiguous EBNA1 binding sites (7421-8042), was PCR amplified fromEBV genomic DNA and cloned into the pGLuc-Basic 2 (New England Biolabs)using the KpnI and HindIII restriction sites, resulting in plasmidpGLuc2-21×FR.

For the transient transfection assay, HEK293T cells were seeded at aconcentration of 4-8×10⁶ cells in a 10 cm plate in Delbecco's ModifiedEagle Medium (DMEM) (Life Technologies Corp.) supplemented with 10%Fetal Bovine Serum (FBS) (Gemini Bio-Products). After overnightincubation, the transfection was performed using Lipofectamine 2000(Life Technologies). 3 ug of pGLuc2-21×FR and 0.6 ug ofpTK-3×FLAG-Myc-EBNA1-VP16AD or p3×FLAG-Myc-CMV-24 (empty vector) wereadded to 0.5 ml Optimem buffer (Life Technologies Corp.). 30 ulLipofectamine was added to a separate 0.5 ml Optimem buffer andincubated for 5 minutes. The DNA and lipofectamine mixtures werecombined and incubated for 20 minutes at room temperature and added dropwise to the 10 cm plate. The cells were then incubated for 6 hours at37° C. The cells were harvested, counted and re-suspended at aconcentration of 2×10⁵ cells/ml and distributed using a MicroFlodispenser (BioTek) in 384-well tissue culture plate (Greiner BioOne), 40ul (8000 cells) per well. 160 nl of solutions of compounds of thedisclosure in DMSO at concentrations ranging from 50 mM to 976 uM wereadded to the cells (10-point 2-fold dilution series, final concentration200 uM-390 nM) using a Janus modular Nanohead dispenser (PerkinElmer,Inc.). Compounds and transfected cells were incubated overnight at 37°C. Gaussia luciferase is secreted into the medium. The top 10 ul of cellmedia from the 384-well transfected HEK293T cells is transferred to awhite opaque 384-well development plate. 10 ul of substrate is added toeach well and incubated for 5 minutes. Bioluminescence is then measuredusing the Envision Multiplate Reader (Perkin Elmer, Inc.). To normalizethe activity of the compounds of the disclosure and to filter toxiccompound, the remaining 30 ul of cell media (including the cells) areincubated with 6 ul resazurin, incubated for 4-6 hours at 37° C. andmeasured using the Envision Multiplate Reader. Data analysis and IC₅₀curves are generated using Prism (GraphPad).

Cell Viability Assay: To further evaluate the cell-based efficacy ofEBNA1 inhibitors, a cell cytotoxicity assay was performed. EBNA1inhibitors should selective kill EBV-positive cell lines (Raji, LCL,C666-1) relative to EBV-negative cell lines (Bjab, DG75, HNE-1). Raji,Bjab, and DG75 were obtained from American Type Tissue Culture (ATCC),C666-1 and HNE-1 were a gift from Anne Lee (Hong Kong University) andthe Lymphoblastic Cell Line (LCL) was obtained by in vitro infection ofB-cells with the B95.8 strain of EBV.

To perform this assay, 40 ul of the different cell lines were seeded ata concentration of 1×10⁵ cells in a clear 384-well plate (4000cell/well). 160 nl of compound at concentrations ranging from 50 mM to976 uM were added to each well (10-point, 2-fold dilution series, finalconcentration 200 uM-390 nM) using a Janus modular Nanohead dispenser(PerkinElmer, Inc.). Cells were incubated for 72 hours in a humidified37° C. incubator 5% CO₂. The cell viability is inferred using theoxidation-reduction indicator, resazurin. 8 ul of resazurin was added toeach well and after 4-6 hours incubation at 37° C., the fluorescentsignal was monitored using 530-560 nm excitation wavelength and 590 nmemission wavelength using the Envision Multiplate Reader.

Data analysis and CC₅₀ (Cytotoxicity Concentration) curves are generatedusing Prism (GraphPad). A selectivity index is calculated by determiningthe ratio of the CC₅₀ from the EBV-negative cell line over the CC₅₀ fromthe EBV-positive cell line.

What is claimed is:
 1. A compound of formula (IX):

or a hydrate, solvate, polymorph, pharmaceutically acceptable salt, orprodrug thereof, wherein: R¹ is selected from the group consisting ofoptionally substituted C₁₋₆ linear alkyl, optionally substituted C₃₋₆branched alkyl, optionally substituted C₃₋₆ cyclic alkyl, optionallysubstituted phenyl, optionally substituted heteroaryl, optionallysubstituted benzyl, optionally substituted heteroaryl methyl,

R² is

R³ is CO₂R^(4d); R^(4d) is selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ linear alkyl, and optionallysubstituted C₃₋₆ branched alkyl; R^(8a), R^(8b), R^(8c), R^(8d), andR^(8e) are each independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ linear alkyl, and optionallysubstituted C₃₋₆ branched alkyl; R^(9a), R^(9b), R^(9c), R^(9d), andR^(9e) are each independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ linear alkyl, and optionallysubstituted C₃₋₆ branched alkyl; L² is (CH₂)_(m); and m is 0, 1, 2, or3.
 2. A compound selected from the group consisting of:2-(1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid;2-(1-methyl-1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid;2-[3-(methoxycarbonyl)-1H-indol-6-yl]-3-(2-phenylethynyl)benzoic acid;2-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid;3-(4-amino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;3-(4-carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;2-(1H-indol-6-yl)-3-(4-methoxy-phenylethynyl)-benzoic acid;3-(4-carbamoyl-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;2-(1H-indol-6-yl)-3-[4-(piperazine-1-carbonyl)-phenylethynyl]-benzoicacid; 3-(4-acetylamino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid;2-(1H-indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]-phenylethynyl}-benzoicacid; 2-(1H-indol-6-yl)-3-(4-methanesulfonylamino-phenylethynyl)-benzoicacid;2-(1H-indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)-phenylethynyl]-benzoicacid;2-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoicacid; 2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoic acid;2-(3-chloro-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid;2-(3-(2-acetamidoethyl)-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoicacid;2-(1H-indol-6-yl)-3-((4-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)benzoicacid; 2-(1H-indol-6-yl)-3-((4-morpholinophenyl)ethynyl)benzoic acid;3((3-carbamoylphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;3((4-Fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;3((2,4-Difluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;3((3-Acetamidophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;2-(1H-indol-6-yl)-3-((3-(nicotinamido)phenyl)ethynyl)benzoic acid;3-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoicacid; 3((3-aminophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;2-(1H-indol-6-yl)-3-((3-(methylsulfonamido)phenyl)ethynyl)benzoic acid;2-(1H-indol-6-yl)-3-((3-(thiophene-2-sulfonamido)phenyl)ethynyl)benzoicacid; 3-((3-acetamido-5-fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoicacid; 3((6-aminopyridin-2-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;3((2-aminopyridin-4-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;3-(4-hydroxybut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;3-(3-amino-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;3-(3-hydroxy-3-phenylprop-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;3-(3-hydroxy-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid;3((3-(hydroxymethyl)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;2-(2-(ethoxycarbonyl)-1H-indol-6-yl)-3-(phenylethynyl)benzoic acid;3-((3-carbamoyl-5-methoxyphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid;3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoicacid; 2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; and3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-6-yl)benzoic acid; or apharmaceutically acceptable salt, carboxylic ester, polymorph or solvatethereof.
 3. A composition comprising at least one compound of claim 1and at least one excipient.
 4. A composition comprising at least onecompound of claim 2 and at least one excipient.
 5. The compound of claim1, wherein R^(4d) is selected from the group consisting of hydrogen,C₁₋₆ linear alkyl, and C₃₋₆ branched alkyl.
 6. The compound of claim 1,wherein R^(4d) is hydrogen.
 7. The compound of claim 1, wherein R^(4d)is selected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
 8. Thecompound of claim 2, wherein the carboxylic ester is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, iso-butyl, and tert-butyl.